A pelvis-oriented margin of stability is robust against deviations in walking direction.

The Margin of Stability (MOS) is often assessed relative to the intended, linear path of walking progression. When an unanticipated or irregular change in direction occurs, such as during a sudden turn or during activities of daily living, distinguishing the lateral from anteroposterior MOS can be challenging. The purpose of this study was to assess an anatomically orientated method of calculating the MOS using the pelvic orientation to define lateral and anteroposterior directions. We hypothesized that when straight walking was disrupted with a curved path, the pelvis-oriented MOS measure would be less variable compared to the global-oriented MOS measure. We recruited 16 unimpaired participants to walk at preferred and fast walking speeds along a straight walking path, as well as a path with an exaggerated, curvilinear deviation. We determined the within-subject mean and standard deviation of the anterior MOS at mid-swing and the posterior and lateral MOS at ipsilateral foot strike. For straight walking and curved walking separately, repeated measures factorial ANOVAs assessed the effects of model (global or pelvis-oriented), limb (left or right), and speed (preferred or fast) on these MOS values. Based on reduced variability during curved walking, the pelvis-oriented MOS was more robust to walking deviations than the globally defined MOS. In straight walking, the pelvis-oriented MOS was characterized by less lateral and more anterior stability with differences exacerbated by faster walking. These results suggest a pelvis-oriented MOS has utility when the path of progression is unknown or unclear.

How should the margin of stability during walking be expressed to account for body size?

When expressing the margin of stability as a distance, it does not directly estimate the perturbation magnitude needed to change stability states. Additionally, it is unknown how body size may influence this measure. Therefore, we propose other expressions of stability margins, including that of an impulse, a change in center of mass velocity, and a scaled, unitless impulse. The purpose of this study was to determine the influence of body size on these margin expressions using walking data from children and adults. We anticipated that margins expressed as an impulse would have strong correlations with body mass and height, as well as large between-group differences. We predicted that scaling this impulse value would result in small correlations and between-group effect sizes. We calculated each stability margin at minimum lateral values and in the anteroposterior directions at mid-swing and foot strike. In the lateral direction, margins expressed as an impulse had strong correlations with body size (r≥0.58, p<0.01) and large between-group differences (|d|≥1.07, p<0.01). The other expressions did not have strong positive correlations (|r|≤0.20) or large between-group effects (|d|≤0.44). In the anteroposterior directions, impulse margins had strong correlations with body size (|r|≥0.83, p<0.01) and large between-group differences (|d|≥1.74, p<0.01). The scaled, unitless impulse margin was the only variable that resulted in small, non-significant differences (|r|≤0.22, p≥0.24) as well as small between-group effect sizes (|d|≤0.46, p≥0.22). We propose expressing stability margins as an impulse. If scaling is needed, we encourage using the scaled, unitless impulse.

Posterior fall-recovery training applied to individuals with chronic stroke: A single-group intervention study.

BACKGROUND: To assess the effects of the initial stepping limb on posterior fall recovery in individuals with chronic stroke, as well as to determine the benefits of fall-recovery training on these outcomes. METHODS: This was a single-group intervention study of 13 individuals with chronic stroke. Participants performed up to six training sessions, each including progressively challenging, treadmill-induced perturbations from a standing position. Progressions focused on initial steps with the paretic or non-paretic limb. The highest perturbation level achieved, the proportion of successful recoveries, step and trunk kinematics, as well as stance-limb muscle activation about the ankle were compared between the initial stepping limbs in the first session. Limb-specific outcomes were also compared between the first and last training sessions. FINDINGS: In the first session, initial steps with the non-paretic limb were associated with a higher proportion of success and larger perturbations than steps with the paretic limb (p = 0.02, Cohen's d = 0.8). Paretic-limb steps were wider relative to the center of mass (CoM; p = 0.01, d = 1.3), likely due to an initial standing position with the CoM closer to the non-paretic limb (p = 0.01, d = 1.4). In the last training session, participants recovered from a higher proportion of perturbations and advanced to larger perturbations (p < 0.05, d > 0.6). There were no notable changes in kinematic or electromyography variables with training (p > 0.07, d < 0.5). INTERPRETATION: The skill of posterior stepping in response to a perturbation can be improved with practice in those with chronic stroke, we were not able to identify consistent underlying kinematic mechanisms behind this adaptation.

SIG1273: a new cosmetic functional ingredient to reduce blemishes and Propionibacterium acnes in acne prone skin.

BACKGROUND: Propionibacterium acnes is a major contributing factor to the inflammatory component of acne. The interaction of P. acnes with keratinocytes leads to an innate immune response via activation of toll-like receptors (TLR2, TLR4) resulting in the production and secretion of pro-inflammatory mediators. SIG1273, an isoprenylcysteine small molecule modulates inflammatory signaling pathways and kills P. acnes. SIG1273 represents a novel cosmetic functional ingredient that provides relief from blemishes in acne prone skin. OBJECTIVE: To assess the keratinocyte response and microbial growth of SIG1273 in vitro and evaluate the tolerability of SIG1273 gel applied topically in acne prone subjects. METHODS: For in vitro studies, human keratinocytes were exposed in culture to live P. acnes and peptidoglycan (PGN) to induce IL-8 production. P. acnes were cultured to determine minimal inhibitory concentration and minimal bactericidal concentration values. A total of 30 subjects were randomized in a double-blind controlled trial receiving 3% SIG1273 gel or vehicle for 6 weeks. Evaluation included inflammatory lesions, noninflammatory lesions, microcomedones, Sebutape scores, and P. acnes counts. RESULTS: In vitro studies demonstrate SIG1273 inhibits P. acnes-induced IL-8 production and inhibits P. acnes growth. SIG1273 gel was well tolerated with no signs of stinging, redness, or itching. Furthermore, improvement in some aspects of acne was observed in subjects applying SIG1273 gel, including inflammatory lesions, microcomedone counts and Sebutape scores. Facial scrubs taken to measure P. acnes colony-forming units showed those applying SIG1273 gel had ~1.0 Log 10 colony reduction over the length of the study, a statistically significantly improvement when compared with vehicle. No significant effects above vehicle were observed for noninflammatory lesions. CONCLUSIONS: SIG1273 represents a novel cosmetic functional ingredient that provides a safe dual modulating benefit to individuals with acne prone skin by reducing P. acnes counts and reducing inflammation.

Investigating clearance mechanisms for recombinant activated factor VII in a perfused liver model.

Clearance mechanisms for recombinant activated human FVII (rFVIIa; NovoSeven), a heterogeneously glycosylated protein, have yet to be fully elucidated, but may involve the liver. The effects of the gamma-carboxy glutamic acid (Gla) domain and the sialic acid content of the protein on rFVIIa clearance were investigated following intravenous administration of rFVIIa lacking the Gla domain, des(1-44) rFVIIa and asialo-rFVIIa in pharmacokinetic (PK) studies and perfused rat livers. PK parameters for both rFVIIa and des(1-44) rFVIIa had similar biphasic clearance profiles, as well as half-lives ([t(1/2)]=80 and 88 minutes, respectively), while asialo-rFVIIa was cleared quickly (t(1/2)=21 minutes) with a linear clearance profile. Perfused liver studies with all proteins (10 nM) mirrored the trends in profiles observed in the PK study. rFVIIa and des(1-44) rFVIIa were cleared to a similar extent, 41% and 35%, respectively, after 1 h, whereas plasma-derived FVII from humans (which has a higher sialylation content than rFVIIa) was cleared to a lesser extent (21%). Asialo-rFVIIa, on the other hand, was almost totally cleared and when an excess of asialo-orosomucoid was added to the perfusate, its clearance was significantly reduced (by 34%) and also for rFVIIa, albeit to a lesser extent (by 14%). Together these data suggest that carbohydrate receptor(s) (e.g. the asialoglycoprotein receptor, ASGPR) play a role in asialo-rFVIIa and rFVIIa clearance. In vivo and liver clearance data correlated well showing similar trends and indicated that rFVIIa clearance is not affected by the Gla domain, but rather by a subpopulation of N-glycosylated structures on rFVIIa.

In silico prediction of membrane permeability from calculated molecular parameters.

A data set consisting of 712 compounds was used for classification into two classes with respect to membrane permeation in a cell-based assay: (0) apparent permeability (P(app)) below 4 x 10(-6) cm/s and (1) P(app) on 4 x 10(-6) cm/s or higher. Nine molecular descriptors were calculated for each compound and Nearest-Neighbor classification was applied using five neighbors as optimized by full cross-validation. A model based on five descriptors, number of flex bonds, number of hydrogen bond acceptors and donors, and molecular and polar surface area, was selected by variable selection. In an external test set of 112 compounds, 104 compounds were classified and 8 compounds were judged as "unknown". Among the 104 compounds, 16 were misclassified corresponding to a misclassification rate of 15% and no compounds were falsely predicted in the nonpermeable class.

Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B.

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.