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.     

Self-selecting albino rats exhibit differential preferences for pure macronutrient diets: Characterization of three subpopulations

Analyses of natural feeding behavior in albino male Sprague-Dawley rats demonstrate that, when allowed to self-select from pure macronutrient diets (protein, carbohydrate and fat), these rats of the same genetic strain can be categorized into 3 subpopulations according to either their 24-h or their 12-h nocturnal patterns of nutrient intake. A majority of the animals (HC for high carbohydrate, 50% of the total population) consumed a diet rich in carbohydrate relative to protein or fat, while a smaller population of rats (HF, 30%) preferred the fat diet, and an even smaller population (HP, 20%) chose a high-protein diet. These 3 subpopulations, after a few weeks of maintenance on the diets, differed in their body weight, with the HF rats having a higher body weight than the HP animals, who tended to weigh more than the lightest HC rats. Whereas all subgroups exhibited a similar bimodal distribution of feeding during the nocturnal cycle, with peaks during the early and late dark periods, they were distinguishable on the basis of their nutrient consumption during specific phases of the dark cycle. This difference was most apparent in the early dark phase, when the 3 subgroups exhibited exaggerated preferences for the specific nutrient that was generally preferred over the 24-h cycle. This is in contrast to the middle dark phase, when diet preferences were attenuated or lost, and the late dark phase, when most rats were similar in showing an increased preference for protein and fat and a decreased preference for carbohydrate. The HF group was further distinguished by an unusually strong burst of feeding during the first 2 h of the dark period and an extra peak of feeding in the middle dark period (7th h), both of which were relatively high in fat content.     

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.     

ROCK inhibitor (Y27632) increases apoptosis and disrupts the actin cortical mat in embryonic avian corneal epithelium.

The embryonic chicken corneal epithelium is a unique tissue that has been used as an in vitro epithelial sheet organ culture model for over 30 years (Hay and Revel [1969] Fine structure of the developing Avian cornea. Basel, Switzerland: S. Karger A.G.). This tissue was used to establish that epithelial cells could produce extracellular matrix (ECM) proteins such as collagen and proteoglycans (Dodson and Hay [1971] Exp Cell Res 65:215-220; Meier and Hay [1973] Dev Biol 35:318-331; Linsenmayer et al. [1977] Proc Natl Acad Sci U S A 74:39-43; Hendrix et al. [1982] Invest Ophthalmol Vis Sci 22:359-375). This historic model was also used to establish that ECM proteins could stimulate actin reorganization and increase collagen synthesis (Sugrue and Hay [1981] J Cell Biol 91:45-54; Sugrue and Hay [1982] Dev Biol 92:97-106; Sugrue and Hay [1986] J Cell Biol 102:1907-1916). Our laboratory has used the model to establish the signal transduction pathways involved in ECM-stimulated actin reorganization (Svoboda et al. [1999] Anat Rec 254:348-359; Chu et al. [2000] Invest Ophthalmol Vis Sci 41:3374-3382; Reenstra et al. [2002] Invest Ophthalmol Vis Sci 43:3181-3189). The goal of the current study was to investigate the role of ECM in epithelial cell survival and the role of Rho-associated kinase (p160 ROCK, ROCK-1, ROCK-2, referred to as ROCK), in ECM and lysophosphatidic acid (LPA) -mediated actin reorganization. Whole sheets of avian embryonic corneal epithelium were cultured in the presence of the ROCK inhibitor, Y27632 at 0, 0.03, 0.3, 3, or 10 microM before stimulating the cells with either collagen (COL) or LPA. Apoptosis was assessed by Caspase-3 activity assays and visualized with annexin V binding. The ROCK inhibitor blocked actin cortical mat reformation and disrupted the basal cell lateral membranes in a dose-dependent manner and increased the apoptosis marker annexin V. In addition, an in vitro caspase-3 activity assay was used to determine that caspase-3 activity was higher in epithelia treated with 10 microM Y-27632 than in those isolated without the basal lamina or epithelia stimulated with fibronectin, COL, or LPA. In conclusion, ECM molecules decreased apoptosis markers and inhibiting the ROCK pathway blocked ECM stimulated actin cortical mat reformation and increased apoptosis in embryonic corneal epithelial cells.     

Bladder acellular matrix as a substrate for studying in vitro bladder smooth muscle-urothelial cell interactions

The objective of this study was to evaluate the ability of bladder acellular matrix (BAM) to support the individual and combined growth of primary porcine bladder smooth muscle (SMC) and urothelial (UEC) cells. An in vitro co-culture system was devised to evaluate the effect of UEC on (i) SMC-mediated contraction of BAM discs, and (ii) SMC invasiveness into BAM. Cells were seeded onto BAM discs under 4 different culture conditions. Constructs were incubated for 1, 7, 14 and 28 days. Samples were then harvested for evaluation of matrix contraction. Immunohistochemistry (IHC) was utilized to examine cellular organization within the samples and conditioned media supernatants analyzed for net gelatinase activity. BAM contraction was significantly increased with co-culture. The same side co-culture configuration lead to a greater reduction in surface area than opposite side co-culture. IHC revealed enhanced SMC infiltration into BAM when co-culture was utilized. A significant increase in net gelatinase activity was also observed with the co-culture configuration. Enhanced infiltration and contractile ability of bladder SMCs with UEC co-culture may, in part, be due to an increase in gelatinase activity. The influence of bladder UECs on SMC behaviour in vitro indicates that BAM may contain some key inductive factors that serve to promote important bladder cell-cell and cell-matrix interactions.     

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.