The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo

Microvascular occlusion in sickle cell disease can be initiated by adhesion of sickle red blood cells (RBCs) to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBCs adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocity (V(RBC)) in mice. We found faster V(RBC) of sickle RBCs in P-selectin knock-out and control mice than in sickle cell mice, which have increased endothelial cell P-selectin expression. Agonist peptide for murine protease-activated receptor-1 (PAR-1), which selectively activates mouse endothelial cells but not platelets, was used to assess the effects of endothelial cell P-selectin on microvascular flow. Suffusion of venules with this agonist stopped flow promptly in normal and sickle mice but not in P-selectin knock-out mice or in control mice pretreated with anti-P-selectin monoclonal antibody or unfractionated heparin (UFH). Agonist-induced slowing of flow was reversed rapidly by suffusion with UFH, provided flow had not already stopped. We conclude that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease and that blocking P-selectin may be useful for preventing painful vasoocclusion in sickle cell disease.     

Speech rhythm in Kannada speaking adults who stutter

Purpose: A longstanding hypothesis about the underlying mechanisms of stuttering suggests that speech disfluencies may be associated with problems in timing and temporal patterning of speech events.

Method: Fifteen adults who do and do not stutter read five sentences, and from these, the vocalic and consonantal durations were measured. Using these, pairwise variability index (raw PVI for consonantal intervals and normalised PVI for vocalic intervals) and interval based rhythm metrics (PercV, DeltaC, DeltaV, VarcoC and VarcoV) were calculated for all the participants.

Result: Findings suggested higher mean values in adults who stutter when compared to adults who do not stutter for all the rhythm metrics except for VarcoV. Further, statistically significant difference between the two groups was found for all the rhythm metrics except for VarcoV.

Conclusion: Combining the present results with consistent prior findings based on rhythm deficits in children and adults who stutter, there appears to be strong empirical support for the hypothesis that individuals who stutter may have deficits in generation of rhythmic speech patterns.     

The epidemiology of child maltreatment

Child maltreatment is a significant worldwide problem, with consequences that can include impaired physical and mental health throughout life, and adverse social and occupational effects that carry a heavy economic and social burden. One estimate of cost to the US economy in 2007, for example, was over US$100bn. In middle- and low-income countries, there have been fewer studies of incidence and prevalence, and the economic and social costs are harder to estimate. It is very difficult to obtain full case ascertainment even in the most severe forms of child maltreatment, and even for fatal cases. In general, self-reporting and surveys identify higher rates of child maltreatment than data from sources relating to official notification. This paper reviews the epidemiology of child maltreatment from a practical perspective, with a focus on factors in the social environment, and the clinical history and examination, that predict an increased risk of child maltreatment.     

Hypertonia in childhood secondary dystonia due to cerebral palsy is associated with reflex muscle activation

It is often assumed that co‐contraction of antagonist muscles is responsible for increased resistance to passive movement in hypertonic dystonia. Although co‐contraction may certainly contribute to hypertonia in some patients, the role of reflex activation has never been investigated. We measured joint torque and surface electromyographic activity during passive flexion and extension movements of the elbow in 8 children with hypertonic arm dystonia due to dyskinetic cerebral palsy. In all cases, we found significant phasic electromyographic activity in the lengthening muscle, consistent with reflex activity. By correlating activation with position or velocity of the limb, we determined that some children exhibit position‐dependent activation, some exhibit velocity‐dependent activation, and some exhibit a mixed pattern of activation. We conclude that involuntary or reflex muscle activation in response to stretch may be a significant contributor to increased tone in hypertonic dystonia, and we conjecture that this activation may be more important than co‐contraction for determining the resistance to passive movement. © 2009 Movement Disorder Society     

Contributors to excess antagonist activity during movement in children with secondary dystonia due to cerebral palsy

Children with secondary dystonia due to cerebral palsy exhibit abnormal upper extremity postures and slow voluntary movement. However, the interaction between abnormal postures and abnormal movement in dystonia is still unclear. Some mechanisms by which postures are maintained in dystonia include stretch reflexes, overflow of muscle activation to other muscles, and direct coactivation of antagonist muscles. This study explored the independent contributions of each of these postural mechanisms to abnormal biceps brachii (antagonist) activity during elbow extension, which slows movement. A linear model of biceps activation as a function of velocity-dependent reflexes, triceps-dependent overflow, and direct drive to the biceps was fitted to experimental data from 11 children and young adults with secondary dystonia due to cerebral palsy and 11 age-matched control subjects. Subjects performed elbow extension movements against each of four levels of resistance without perturbations or in each of two perturbation conditions. Results show that biceps activity in children with dystonia consists of significant contributions of reflex activation, overflow from triceps, and direct muscular drive. Additionally, stretch reflexes during movement are shown to be elevated at three latencies after stretch. These findings suggest that there are postural mechanisms involved in stabilizing the elbow along its slow trajectory during movement and provide a quantitative basis for the selection of treatments targeting specific impairments in children with secondary dystonia due to cerebral palsy.     

Fear conditioning can contribute to behavioral changes observed in a repeated stress model

Repeated exposure to laboratory stressors often results in behavioral changes that are commonly referred to as depressive-like behaviors. Here, we examined the contribution fear conditioning may play in altering an animals' behavior in a repeated stress paradigm. Fischer rats were exposed daily to different stressors in a complex environment (context A). After four days of stressor exposure, exploratory behavior (10 min in new cage) and social interaction (5 min with juvenile) were tested on day 5 in either the same environment or a new environment (context B). Rats showed decreased exploration and social interaction when tested in context A compared to control rats or rats tested in context B. Additionally, chronic infusion of propranolol (beta-adrenergic receptor antagonist that crosses the blood-brain barrier), but not nadolol (beta-adrenergic receptor antagonist that does not readily cross the blood-brain barrier), prevented the behavioral changes following repeated stressor exposure. Propranolol treatment did not affect the acute or chronic elevation of corticosterone, the decrease in body weight gain, or adrenal hypertrophy observed in animals exposed to stress. These data demonstrate that conditioned fear responses can contribute to behavioral changes in a repeated stress paradigm. Additional studies revealed, Sprague-Dawley rats do not demonstrate decreased exploration or social interaction when testing occurs in the same context as repeated stressor exposure suggesting Fischer rats may have a greater propensity to associate distal cues with aversive events in a complex environment. This may be due to greater stress responses in Fischer animals that are known to enhance consolidation of emotionally arousing events.     

Influence of mood state on capacity to consent to research in patients with bipolar disorder

OBJECTIVES: Experts have debated the ability of patients with bipolar illness to consent to research participation when manic. We compared 25 euthymic bipolar and 26 manic bipolar patients in their understanding of three hypothetical studies of varying complexity. METHODS: Hypothetical studies were presented as written informed consent forms, which were reread up to three times. Questions included assessment of hypothetical study purposes, procedures, risks and benefits, and voluntariness of participation. RESULTS: After adjusting for educational level, subjects with mania had lower mean understanding scores for all three hypothetical studies compared to euthymic subjects on initial assessment. By the end of Trial 3 of each hypothetical study, there were no significant differences between groups. The proportion of subjects with mania who met predetermined pass criteria for sufficient understanding was lower than the proportion of euthymic subjects on initial assessment of the first hypothetical study, but not the other hypothetical studies (odds ratio = 0.24; 95% confidence interval = 0.07-0.8; p = 0.02). Both groups exhibited an increase in the pass proportion by the end of the third trial for each hypothetical study with no significant differences between groups. CONCLUSIONS: We conclude that subjects with mania exhibited significantly poorer levels of understanding of relevant information in hypothetical research consent forms compared to euthymic subjects when initially presented with research information. The improvement in manic patients' understanding scores with the iterative review of consent forms suggests that many manic patients may be able to consent to research protocols containing an educational intervention as a part of the informed consent process.     

Visualising structural and functional characteristics distinguishing between newly diagnosed high-tension and low-tension glaucoma patients

Purpose

To determine whether there are quantifiable structural or functional differences that can distinguish between high-tension glaucoma (HTG; intraocular pressure [IOP] > 21 mm Hg) and low-tension glaucoma (LTG; IOP ≤ 21 mm Hg) at diagnosis.

Method

This was a retrospective, cross-sectional study. Clinical results of one eye from 90 newly diagnosed HTG and 319 newly diagnosed LTG patients (117 with very-low-tension glaucoma [vLTG; ≤15 mm Hg] and 202 with middling LTG [mLTG; >15 mm Hg, ≤21 mm Hg]) were extracted, which included relevant demographic covariates of glaucoma, quantitative optical coherence tomography (including the optic nerve head, retinal nerve fibre layer and ganglion cell-inner plexiform layer) measurements and standard automated perimetry global metrics. We used binary logistic regression analysis to identify statistically significant clinical parameters distinguishing between phenotypic groups for inclusion in principal component (PC) (factor) analysis (PCA). The separability between each centroid for each cohort was calculated using the Euclidean distance (d(x,y)).

Results

The binary logistic regression comparing HTG and all LTG identified eight statistically significant clinical parameters. Subsequent PCA results included three PCs with an eigenvalue >1. PCs 1 and 2 accounted for 21.2% and 20.2% of the model, respectively, with a d(x,y) = 0.468, indicating low separability between HTG and LTG. The analysis comparing vLTG, mLTG and HTG identified 15 significant clinical parameters, which were subsequently grouped into five PCs. PCs 1 and 2 accounted for 24.1% and 17.8%, respectively. The largest separation was observed between vLTG and HTG (d(x,y) = 0.581), followed by vLTG and mLTG (d(x,y) = 0.435) and lastly mLTG and HTG (d(x,y) = 0.210).

Conclusion

Conventional quantitative structural or functional parameters could not distinguish between pressure-defined glaucoma phenotypes at the point of diagnosis and are therefore not contributory to separating cohorts. The overlap in findings highlights the heterogeneity of the primary open-angle glaucoma clinical presentations among pressure-defined groups at the cohort level.