Association of haplotypes in the beta-chemokine locus with multiple sclerosis

Linkage studies in multiple sclerosis (MS) identified several susceptibility loci. One of these regions includes chromosome 17q11 where a meta-analysis of data from three genome scans suggested linkage. This region encodes a cluster of genes for beta-chemokines or CC chemokine ligands (CCLs), which may be involved in the development of MS lesions. Here we aimed to test if CCL alleles and haplotypes are associated with MS. Using methods of linkage and association, we observed deviations from the expected 50% transmission of haplotypes from unaffected parents to their affected children at CCL2, CCL11-CCL8-CCL13 and CCL3 within the investigated 1.85 MB chromosomal segment. Analyses of the linkage disequilibrium map support that variants with possible relevance to MS can be located within these subregions. Identification of MS associated CCL variants may have direct clinical significance, as it can lead to the design of small competitive antagonists of these molecules with beneficial effects in the treatment of patients with early and active disease.     

The Prediction of Intracranial Injury After Minor Head Trauma in the Pediatric Population

Reference: Dunning J, Batchelor J, Stratford-Smith P, et al. A meta-analysis of variables that predict significant intracranial injury in minor head trauma. Arch Dis Child. 2004;89:653–659.Clinical Question: Which clinical signs or symptoms of minor head trauma are predictive of intracranial hemorrhage in children and adolescents?Data Sources: Investigations were identified by MEDLINE and EMBASE searches from 1990 through 2002 by a search of the grey literature and by contacting experts for additional papers. The search terms were selected to find all studies reporting intracranial hemorrhage (ICH) or complications after head trauma.Study Selection: A full systematic review was conducted, and all cohort or nested cohort studies that presented data on minor head injuries in children less than 18 years old, with or without ICH, were identified. Studies were then judged for inclusion based on the presentation of a series of at least 100 patients and a documented reliable standard for the detection of ICH for all patients in the study. The use of computed tomography (CT) and medical follow-up was considered an acceptable gold standard. Intracranial hemorrhage was defined as any abnormality detected on the CT scan due to the traumatic presence of extravascular blood. Minor head trauma was defined as patients presenting with a Glasgow Coma Scale (GCS) score of 13–15.Data Extraction: Seven clinical correlates were used for data extraction, including skull fracture, headache, vomiting, focal neurology, seizure, loss of consciousness, and a GCS score of less than 15. Data were analyzed using a pooled estimate of the relative risk ratio with a random-effects model.Main Results: The searches identified a total of 2134 studies for the initial review. After an abstract review by 2 independent examiners, 98 studies were identified for a full-paper review. Each study was graded on a 4-point scale according to the level of evidence provided, using scales consistent with the Oxford Centre for Evidence-Based Medicine and the National Institute for Clinical Excellence. Thirty-four of these articles were of adequate quality for inclusion; however, many did not include data that could be separated into a specific data set for children, had too small a sample size, or lacked enough data on individual correlates to head trauma. Nineteen studies provided data on children, but 3 of these were excluded due to poor quality or lack of a reported CT scan, leaving a total of 16 studies for the meta-analysis.The analysis included a total of 22 420 patients ranging between 0 and 18 years of age. The meta-analysis showed a significant increased relative risk of ICH for patients sustaining loss of consciousness (2.23), GCS <15 (5.51), skull fracture (6.13), and focal neurology (9.43). No significant increases in risk for headache (1.02), vomiting (0.878), or seizure (2.82) were noted; however, heterogeneity was significant for this last correlate. The prevalence of ICH ranged from 1.3 to 36%, supporting the notion of a large amount of heterogeneity or variability in the inclusion criteria among the studies.Conclusions: These findings demonstrate that loss of consciousness, decreased level of consciousness (GCS <15), skull fracture, and focal neurology are risk factors for ICH in the pediatric population. However, these findings are not definitive enough to establish pediatric head-injury guidelines regarding CT scanning or admission to hospital after minor head trauma.COMMENTARYAlthough intracranial hemorrhage (ICH) after mild head injury is a rare occurrence in athletes, certified athletic trainers (ATCs) must be aware of the signs and symptoms of all severities of head trauma, including ICH. The initial role of the ATC when there is a suspected head injury is the detection of focal traumatic brain injury (TBI), including epidural hematoma, subdural hematoma, cerebral contusion, and intracerebral hemorrhage and hematoma.^1,2 To successfully recognize these potentially life-threatening head injuries, the ATC must understand the various presentations of athletes with head injuries and the signs and symptoms that often accompany them, such as loss of consciousness (LOC), cranial nerve deficits, decreasing mental status, and worsening symptoms.¹Dunning et al³ presented a meta-analysis that has direct relevance to the practice of athletic training and the management of minor head injuries. Understanding the potential risk factors for ICH is an important step in ensuring adequate referral to medical professionals and a quick diagnosis of possible ICH. Often, the ATC must decide whether an athlete should be referred to the emergency room once he or she has sustained a mild head injury and, once at the emergency room, physicians need to decide on a course of diagnostics. This is even more of a concern in the pediatric athlete because of the potential for both short-term and long-term complications in the still-developing brain.^4–7 As a general rule, failure of an athlete''s mental status to clear rapidly should lead to a referral for neuroimaging.⁸ With the suspicion of focal TBI, CT scans have been recommended as the neuroimaging modality of choice because they can easily detect acute blood collection and skull fracture.⁸It is important to note that differences exist between sport-related minor head trauma and minor head trauma from additional mechanisms, such as motor vehicle accidents, falls, and other accidents. None of the studies used by Dunning et al³ were investigations of sport-related minor head injury. Minor head injuries that produce ICH or any of the clinical correlates found to be significant predictors of ICH (LOC, focal neurology, Glasgow Coma Scale [GCS] <15, or skull fracture) are rare in athletes.² In fact, recent authors have reported that only 6.3 to 8.9% of collegiate athletes experienced LOC after a concussion.^9–11 Regardless of the rarity of focal TBI and injuries that result in ICH during athletics, it is imperative that these injuries be ruled out by the ATC.Based on this meta-analysis, the correlates identified as predictors of ICH included LOC, a GCS score of <15, focal neurology, and a skull fracture. Fortunately, the presence of these clinical signs and symptoms in an athlete would warrant physician referral based on the recommendations made in the National Athletic Trainers'' Association position statement on sport-related concussion and other recommendations for on-field management of head trauma.^1,2,8 Even though headache and vomiting were not predictive of ICH, documenting these and other signs and symptoms of mild head trauma should be part of the ATC''s assessment protocol.^1,12,13 By quantifying the number of signs and symptoms present as well as the frequency and/or duration of these signs and symptoms, the ATC can track the recovery of the athlete and use the information for referral if the athlete does not demonstrate improvement. In addition, the ATC should use age-appropriate adjunct assessments, including neurocognitive testing^7,14–18 (traditional pen-and-paper neuropsychological tests, ImPACT [Immediate Postconcussion Assessment and Cognitive Testing, University of Pittsburgh Medical Center, Pittsburgh, PA], ANAM [Automated Neuropsychological Assessment Metrics, National Rehabilitation Hospital Assistive Technology and Neuroscience Center, Washington, DC], Concussion Resolution Index [HeadMinder Inc, New York, NY], Standardized Assessment of Concussion [CNS Inc, Waukesha, WI]) and postural stability testing¹⁸ to aid in the decision-making process.The findings of Dunning et al³ provide insight into specific risk factors the ATC should look for when evaluating minor head trauma in children and adolescents. The presence of any of the significant predictors should warrant immediate referral. The authors also acknowledge that other signs and symptoms (eg, dizziness, drowsiness, confusion) could be predictive of ICH; however, these factors had not been adequately investigated in the pediatric literature identified for this meta-analysis and therefore were not included. This factor, along with the variability in the inclusion criteria, timing of CT scans, and differences in the ICH definitions in the individual studies are limitations of this meta-analysis. Another potential limitation regarding the predictive value of the headache variable to ICH stems from a lack of information regarding the severity of the headaches reported in the individual studies. Some evidence suggests a relationship between severe headaches and ICH¹⁹; therefore, headache severity should also be questioned during the clinical examination. Several other limitations of this meta-analysis include no listing of specific medical subject headings terms used to search the databases, not describing the duration of LOC from the various studies used, and not adequately describing or defining the specific types of focal neurology used as a correlate. However, other authors have described focal neurologic changes as including posturing and dilating pupils.²Although this meta-analysis offers medical professionals working with children and adolescents one interpretation of the evidence regarding clinical risk factors predictive of ICH, it does not provide strong enough evidence to alter the current head-injury management and CT scanning protocols for children.²⁰ Future studies should address the limitations outlined by Dunning et al³ to better determine the predictive value of various clinical signs and symptoms of minor head trauma in the pediatric population.     

First Case of Subcutaneous Phaeohyphomycosis Caused by Scytalidium lignicola in a Human

A case of subcutaneous phaeohyphomycosis in a human, involving the ankle and caused by Scytalidium lignicola, is described. The isolate was found to be sensitive to amphotericin B, 5-fluorocytosine, miconazole, and ketoconazole in vitro.     

Fooling the brain into thinking it sees both hands moving enhances bimanual spatial coupling

This study examined the hypothesis that the mirror reflection of one hands movement directly influences motor output of the other (hidden) hand, during performance of bimanual drawing. A mirror was placed between the two hands during bimanual circle drawing, with one hand and its reflection visible and the other hand hidden. Bimanual spatial coupling was enhanced by the mirror reflection, as shown by measures of circle size. Effects of the mirror reflection differed significantly from effects of vision to one hand alone, but did not differ from a control task performed in full vision. There was no evidence of a consistent phase lead of the visible hand, which indicates that the observed effects on spatial coupling were immediate and not based on time-consuming feedback processes. We argue that visual mirror symmetry fools the brain into believing it sees both hands moving rather than one. Consequently, the spatial properties of movement of the two hands become more similar through a process that is virtually automatic.     

Positive illusory bias and the self-protective hypothesis in children with learning disabilities.

We tested the hypothesis that overestimations of performance by children with learning disabilities (LD) are self-protective and will dissipate following positive feedback. Twenty-three boys and 17 girls with LD (ages 10.6 to 13.5 years) and a control group of non-LD matched children (22 boys and 17 girls) provided a prediction of their performance on a spelling test prior to completing the test. Subsequently, they were randomly assigned to either a positive feedback or a no-feedback condition. Finally, they provided a second prediction of performance on an equivalent spelling test. In children with LD, there was a positive bias in their predictions of performance, and, following positive feedback, their predictions became accurate. In children without LD, there was no positive bias and no effect of feedback. The results provide further support for the presence of a positive illusory bias and for the self-protective hypothesis in children with LD.     

Estimation of hand preshaping during human grasping

A new method for evaluating hand preshaping during reaching-to-grasp movement is proposed. The method makes use of all five fingers in estimation of prehension. The investigation was performed on six healthy subjects grasping three different objects at various positions and orientations. The objects were presented to the subjects by means of a robot, which also induced perturbations in both object position and orientation. Positions of markers attached to the finger-tips and dorsum of the hand were recorded by means of a 3D optical tracking system. In the data analysis, the adjacent fingertips were interconnected, thus obtaining a planar pentagon whose various characteristics were investigated and discussed. New parameters for the evaluation of finger preshaping, such as pentagon surface area, angle between the pentagon and hand normal vectors, and the angle between the pentagon and object normal vectors were introduced. The proposed pentagon approach is expected to be useful in future work when examining grasping abilities of subjects with neuromuscular disorders.     

Chondroitin sulfate A released from platelets blocks RANTES presentation on cell surfaces and RANTES-dependent firm adhesion of leukocytes

The sequestration of chemokines on the surface of microvascular endothelium is an early event in the selective recruitment of leukocytes. The sequestration and presentation of chemokines must be tightly controlled to confine the extravasation of leukocytes and to prevent uncontrolled inflammation. We investigated whether soluble molecules released under physiological conditions could control chemokine immobilization on cell surfaces and function as regulatory chemokine binding molecules. We determined that human serum contains a molecule that suppresses RANTES (CCL5) binding to endothelial cells, PBMC and CHO cells. Using platelet-rich and platelet-free plasma, serum from patients with thrombocytopenia, and purified platelets, we identified platelets as the source of the chemokine-binding molecule and further identified it as chondroitin sulfate A. In contrast to platelet-derived fully-sulfated chondroitin sulfate A, low-sulfated chondroitin sulfate A present in plasma was almost inactive. Under physiological flow conditions chondroitin sulfate A was found to block RANTES-mediated firm adhesion of monocytes to endothelial cells. It also prevented RANTES-mediated influx of calcium in CCR5-transfected CHO cells while internalization of CCR5 was only marginally reduced. Taken together, chondroitin sulfate A released from platelets appears to act as an important regulatory molecule for cellular responses to chemokines.     

Nest building in nulligravid,primigravid and primiparous C57BL/6J and DBA/2J mice (Mus musculus)

C57BL/6J (B6) and DBA/2J (D2) mice differ in maternal behavior and nest building, but previous observations on nest building appear to be contradictory. Lactating B6 females spent more time nest building than lactating D2 females [Physiol. Behav. 67 (1999) 599.]; however, pregnant D2 females have been reported to build better nests than pregnant B6 females [Physiol. Behav. 29 (1982) 153.]. To resolve this apparent discrepancy, virgin B6 and D2 females were mated, and the nest quality of nulligravid, primigravid and lactating primiparous females was compared between groups and with that of virgin females. There were no strain differences in the nest ratings of virgin or mated nulligravid females, nor did these groups differ within strains. Pregnant and lactating females of both strains built better nests than nonpregnant females. There was an increase in nest ratings in both strains on the day of parturition. The nest ratings of pregnant and lactating females were higher in B6 than D2 females. The largest strain differences were observed between pregnant B6 and D2 females. One hypothesis to account for these results is that females of these two strains differ in their levels of or sensitivity to hormones during pregnancy and parturition.