Defining the neuroanatomic basis of motor coordination in children and its relationship with symptoms of attention-deficit/hyperactivity disorder.

BACKGROUND: When children have marked problems with motor coordination, they often have problems with attention and impulse control. Here, we map the neuroanatomic substrate of motor coordination in childhood and ask whether this substrate differs in the presence of concurrent symptoms of attention-deficit/hyperactivity disorder (ADHD). METHOD: Participants were 226 children. All completed Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)-based assessment of ADHD symptoms and standardized tests of motor coordination skills assessing aiming/catching, manual dexterity and balance. Symptoms of developmental coordination disorder (DCD) were determined using parental questionnaires. Using 3 Tesla magnetic resonance data, four latent neuroanatomic variables (for the cerebral cortex, cerebellum, basal ganglia and thalamus) were extracted and mapped onto each motor coordination skill using partial least squares pathway modeling. RESULTS: The motor coordination skill of aiming/catching was significantly linked to latent variables for both the cerebral cortex (t = 4.31, p < 0.0001) and the cerebellum (t = 2.31, p = 0.02). This effect was driven by the premotor/motor cortical regions and the superior cerebellar lobules. These links were not moderated by the severity of symptoms of inattention, hyperactivity and impulsivity. In categorical analyses, the DCD group showed atypical reduction in the volumes of these regions. However, the group with DCD alone did not differ significantly from those with DCD and co-morbid ADHD. CONCLUSIONS: The superior cerebellar lobules and the premotor/motor cortex emerged as pivotal neural substrates of motor coordination in children. The dimensions of these motor coordination regions did not differ significantly between those who had DCD, with or without co-morbid ADHD.

Should pharmacologists care about alternative splicing? IUPHAR Review 4.

Alternative splicing of mRNAs occurs in the majority of human genes, and most differential splicing results in different protein isoforms with possibly different functional properties. However, there are many reported splicing variations that may be quite rare, and not all combinatorially possible variants of a given gene are expressed at significant levels. Genes of interest to pharmacologists are frequently expressed at such low levels that they are not adequately represented in genome-wide studies of transcription. In single-gene studies, data are commonly available on the relative abundance and functional significance of individual alternatively spliced exons, but there are rarely data that quantitate the relative abundance of full-length transcripts and define which combinations of exons are significant. A number of criteria for judging the significance of splice variants and suggestions for their nomenclature are discussed.

Short-term effects of military fog oil on the fountain darter (Etheostoma fonticola).

Toxicity tests evaluated chronic and sublethal effects of fog oil (FO) on a freshwater endangered fish. FO is released during military training as an obscurant smoke that can drift into aquatic habitats. Fountain darters, Etheostoma fonticola, of four distinct life stages were exposed under laboratory conditions to three forms of FO. FO was vaporized into smoke and allowed to settle onto water, violently agitated with water, and dosed onto water followed by photo-oxidization by ultraviolet irradiation. Single smoke exposures of spawning adult fish did not affect egg production, egg viability, or adult fish survival in 21-day tests. Multiple daily smoke exposures induced mortality after 5 days for larvae fish. Larvae and juvenile fish were more sensitive than eggs in 96-h lethal concentration (LC50) tests with FO­water mixtures and photo-oxidized FO. Water-soluble FO components photo-modified by ultraviolet radiation were the most toxic, thus indicating the value of examining weathering and aging of chemicals for the best determination of environmental impact.

Impingement and stability of total hip arthroplasty versus femoral head resurfacing using a cadaveric robotics model.

We identified and compared the impingent-free range of motion (ROM) and subluxation potential for native hip, femoral head resurfacing (FHR), and total hip arthroplasty (THA). These constructs were also compared both with and without soft tissue to elucidate the role of the soft tissue. Five fresh-frozen bilateral hip specimens were mounted to a six-degree of freedom robotic manipulator. Under load-control parameters, in vivo mechanics were recreated to evaluate impingement free ROM, and the subluxation potential in two "at risk" positions for native hip, FHR, and THA. Impingement-free ROM of the skeletonized THA was greater than FHR for the anterior subluxation position. For skeletonized posterior subluxations, stability for THA and FHR constructs were similar, while a different pattern was observed for specimens with soft tissues intact. FHR constructs were more stable than THA constructs for both anterior and posterior subluxations. When the femoral neck is intact the joint has an earlier impingement profile placing the hip at risk for subluxation. However, FHR design was shown to be more stable than THA only when soft tissues were intact.

The Concise Guide to PHARMACOLOGY 2013/14: overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Spinal fractures in current military deployments.

OBJECTIVE: To describe spinal fracture patterns presenting to deployed medical facilities during recent military operations. METHODS: Retrospective analysis of the United Kingdom Centre for Defence Imaging Computed Tomography database, 2005-2009. Fractures are classified, mechanism noted and associated injuries recorded. Statistical analysis is by Fisher's Exact test. RESULTS: 128 fractures in 57 casualties are analysed. Ballistic (79%) and non-ballistic mechanisms contribute to vertebral fracture at all regions of the spinal column in patients treated at deployed medical facilities. There is a high incidence of lumbar spine fractures, which are more likely to be due to explosion than gunshot wounding (p < 0.05). Two thirds of thoracolumbar spine fractures caused by explosive devices are unstable and are mainly burst-fractures in configuration. 60% of spinal fracture patients had concomitant injuries. There is a strong relationship between spinal fractures caused by explosions and lower limb fractures. CONCLUSION: Injuries to the spine caused by explosive devices account for greater numbers, greater associated morbidity and increasing complexity than other means of spinal injury managed in contemporary warfare. With the predominance of explosive injury in current conflict, this work provides the first detail of an evolving injury mechanism with implications for injury mitigation research.

Accurate placement of a pelvic binder improves reduction of unstable fractures of the pelvic ring.

The aim of this study was to assess the accuracy of placement of pelvic binders and to determine whether circumferential compression at the level of the greater trochanters is the best method of reducing a symphyseal diastasis. Patients were identified by a retrospective review of all pelvic radiographs performed at a military hospital over a period of 30 months. We analysed any pelvic radiograph on which the buckle of the pelvic binder was clearly visible. The patients were divided into groups according to the position of the buckle in relation to the greater trochanters: high, trochanteric or low. Reduction of the symphyseal diastasis was measured in a subgroup of patients with an open-book fracture, which consisted of an injury to the symphysis and disruption of the posterior pelvic arch (AO/OTA 61-B/C). We identified 172 radiographs with a visible pelvic binder. Five cases were excluded due to inadequate radiographs. In 83 (50%) the binder was positioned at the level of the greater trochanters. A high position was the most common site of inaccurate placement, occurring in 65 (39%). Seventeen patients were identified as a subgroup to assess the effect of the position of the binder on reduction of the diastasis. The mean gap was 2.8 times greater (mean difference 22 mm) in the high group compared with the trochanteric group (p < 0.01). Application of a pelvic binder above the level of the greater trochanters is common and is an inadequate method of reducing pelvic fractures and is likely to delay cardiovascular recovery in these seriously injured patients.

A retrospective study into the levels of evidence presented at the Combined Services Orthopaedic Society annual meeting.

OBJECTIVES: The role of Evidence Based Medicine in clinical care is to provide a framework for the integration of expertise, current evidence and the needs of the individual patient. Research presented at scientific meetings is an important source of such evidence, informing clinical decision making both on military operations and in home nation health care systems. The aim of this study is to review the levels of evidence presented at the Combined Services Orthopaedic Society (CSOS) and two other related scientific meetings. METHODS: Retrospective review of abstracts presented at the annual scientific meetings of the CSOS, Society of Military Orthopaedic Surgeons (SOMOS) and the British Trauma Society (BTS). Basic science studies, animal studies, cadaveric studies, surveys and guest lectures were excluded. Research abstracts were categorised according to the Centre for Evidence-Based Medicine's (CEBM) hierarchy of evidence. Statistical comparison was performed to investigate differences in evidence levels presented at each scientific meeting and between each year of the CSOS meeting. RESULTS: 596 abstracts met the inclusion criteria for this study (179 CSOS, 173 SOMOS, 244 BTS). Level IV evidence accounted for the majority of presented abstracts at each meeting (72.6% CSOS, 69.4% SOMOS, 68.9% BTS). Level I evidence was uncommon at each meeting (6.1% CSOS, 5.2% SOMOS, 2.9% BTS). There was no statistical difference in the evidence levels presented at the three scientific meetings. CONCLUSIONS: The proportion of comparative clinical studies (Levels I-III) presented at military or trauma societies' scientific meetings reflects the difficulty of performing research in emergency surgery. This is further exacerbated in the military environment where operational commitments and delivery of care take priority. However, the future value of comparative clinical research in battlefield healthcare could have an enduring legacy that shapes trauma care for many decades.

The effect of post-operative mechanical axis alignment on the survival of primary total knee replacements after a follow-up of 15 years.

Correct positioning and alignment of components during primary total knee replacement (TKR) is widely accepted to be an important predictor of patient satisfaction and implant durability. This retrospective study reports the effect of the post-operative mechanical axis of the lower limb in the coronal plane on implant survival following primary TKR. A total of 501 TKRs in 396 patients were divided into an aligned group with a neutral mechanical axis (± 3°) and a malaligned group where the mechanical axis deviated from neutral by > 3°. At 15 years' follow-up, 33 of 458 (7.2%) TKRs were revised for aseptic loosening. Kaplan-Meier survival analysis showed a weak tendency towards improved survival with restoration of a neutral mechanical axis, but this did not reach statistical significance (p = 0.47). We found that the relationship between survival of a primary TKR and mechanical axis alignment is weaker than that described in a number of previous reports.

Infection in conflict wounded.

Although mechanisms of modern military wounding may be distinct from those of ancient conflicts, the infectious sequelae of ballistic trauma and the evolving microbial flora of war wounds remain a considerable burden on both the injured combatant and their deployed medical systems. Battlefield surgeons of ancient times favoured suppuration in war wounding and as such Galenic encouragement of pus formation would hinder progress in wound care for centuries. Napoleonic surgeons eventually abandoned this mantra, embracing radical surgical intervention, primarily by amputation, to prevent infection. Later, microscopy enabled identification of microorganisms and characterization of wound flora. Concurrent advances in sanitation and evacuation enabled improved outcomes and establishment of modern military medical systems. Advances in medical doctrine and technology afford those injured in current conflicts with increasing survivability through rapid evacuation, sophisticated resuscitation and timely surgical intervention. Infectious complications in those that do survive, however, are a major concern. Addressing antibiotic use, nosocomial transmission and infectious sequelae are a current clinical management and research priority and will remain so in an era characterized by a massive burden of combat extremity injury. This paper provides a review of infection in combat wounding from a historical setting through to the modern evidence base.

Variation in bone mineral density by anatomical site in patients with proximal humeral fractures.

Low-energy fractures of the proximal humerus indicate osteoporosis and it is important to direct treatment to this group of patients who are at high risk of further fracture. Data were prospectively collected from 79 patients (11 men, 68 women) with a mean age of 69 years (55 to 86) with fractures of the proximal humerus in order to determine if current guidelines on the measurement of the bone mineral density at the hip and lumbar spine were adequate to stratify the risk and to guide the treatment of osteoporosis. Bone mineral density measurements were made by dual-energy x-ray absorptiometry at the proximal femur, lumbar spine (L2-4) and contralateral distal radius, and the T-scores were generated for comparison. Data were also collected on the use of steroids, smoking, the use of alcohol, hand dominance and comorbidity. The mean T-score for the distal radius was -2.97 (SD 1.56) compared with -1.61 (SD 1.62) for the lumbar spine and -1.78 (SD 1.33) for the femur. There was a significant difference between the mean lumbar and radial T scores (1.36 (1.03 to 1.68); p < 0.001) and between the mean femoral and radial T-scores (1.18 (0.92 to 1.44); p < 0.001). The inclusion of all three sites in the determination of the T-score increased the sensitivity to 66% compared with that of 46% when only the proximal femur and lumbar spine were used. This difference between measurements in the upper limb compared with the axial skeleton and lower limb suggests that basing risk assessment and treatment on only the bone mineral density taken at the hip or lumbar spine may misrepresent the extent of osteoporosis in the upper limb and the subsequent risk of fracture at this site. The assessment of osteoporosis must include measurement of the bone mineral density at the distal radius to avoid underestimation of osteoporosis in the upper limb.

Glomus tumour following a total knee replacement: a case report.

Pain following total knee replacement (TKR) is a common problem and cause of poor satisfaction amongst patients. We report on a glomus tumour causing pain on the anterolateral aspect of the knee, 2 years after an otherwise successful total knee replacement for osteoarthritis. The tumour was treated by excision biopsy under general anaesthesia and the diagnosis confirmed by histopathological examination. The removal of the tumour relieved the pain and the patient regained good function. We conclude that a thorough clinical assessment of a patient with a painful knee following TKR is essential to detect and treat coincidental painful pathology.

Management of a complex hind foot war injury with negative pressure wound therapy: a case study.

We report the use of Negative Pressure Wound Therapy (NPWT) in a 39 year old patient with a complex open hind foot injury. The patient sustained an open calcaneal fracture with extensive soft tissue damage following the detonation of an explosively formed penetrating round in a confined space. A remarkable recovery was made following surgical debridement, internal fixation of the fracture and use of NPWT over the soft tissue injury. The patient returned to his normal level of function, without complications within a few months.

International Union of Pharmacology. XXVII. Classification of cannabinoid receptors.

Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

International Union of Pharmacology. XXXI. Recommendations for the nomenclature of multimeric G protein-coupled receptors.

A receptor is defined by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) as a protein, or a complex of proteins, which recognizes physiologically relevant ligands that can regulate the protein to mediate cellular events (Ruffolo et al., 2000). This definition does not include associated proteins, which are not required for agonist recognition and/or receptor assembly. Thus, G proteins are not included in the nomenclature of G protein-coupled receptors (GPCRs). Similarly, proteins which modify receptor disposition, such as proteins with a PDZ domain (Sheng and Sala, 2001), and which associate with the cytosolic portion of the receptor are not included. The question arises, however, as to the way to name multimeric receptors where subunits influence receptor assembly and agonist recognition. The essential issue is whether to name the individual proteins or the association of proteins? NC-IUPHAR recommends that, where possible, the functional receptor complex be given a different name from that of the subunits.

International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function.

The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

The parathyroid hormone 2 (PTH2) receptor.

The human PTH2 receptor binds and is activated at high potency by PTH and by the recently discovered peptide tuberoinfundibular peptide of 39 residues (TIP39). Rat and zebrafish PTH2 receptors are more weakly activated by PTH, suggesting that TIP39 may be the natural ligand for the PTH2 receptor. Unlike the PTH1 receptor, the PTH2 receptor interacts extremely weakly with parathyroid hormone-related peptide (PTHrP). The PTH2 receptor is strongly coupled to stimulation of cAMP accumulation, and more weakly, in a cell-specific manner to increases in intracellular calcium concentration. A variety of evidence supports the general model of receptor amino terminal sequences binding ligand carboxyl terminal sequences with high affinity, and ligand amino terminal sequences activating the receptor through interaction with the "juxtamembrane" portion of the receptor. The receptor is present at greatest levels in the nervous system. It is expressed in scattered cells in the cerebral cortex and basal ganglia and at relatively high abundance in the septum, midline thalamic nuclei, several hypothalamic nuclei, and the dorsal horn of the spinal cord. Peripherally, expression in pancreatic islet somatostatin cells is most dramatic. Functional hypotheses based on the receptor's distribution are being tested. Recent data support involvement in hypothalamic releasing-factor secretion and pain.

Cloning and characterization of 13 novel transcripts and the human RGS8 gene from the 1q25 region encompassing the hereditary prostate cancer (HPC1) locus.

The aim of this study was to develop a saturated transcript map of the region encompassing the HPC1 locus to identify the susceptibility genes involved in hereditary prostate cancer (OMIM 176807) and hyperparathyroidism-jaw tumor syndrome (OMIM 145001). We previously reported the generation of a 6-Mb BAC/PAC contig of the candidate region and employed various strategies, such as database searching, exon-trapping, direct cDNA hybridization, and sample sequencing of BACs, to identify all potential transcripts. These efforts led to the identification and precise localization on the BAC contig of 59 transcripts representing 22 known genes and 37 potential transcripts represented by ESTs and exon traps. Here we report the detailed characterization of these ESTs into full-length transcript sequences, their expression pattern in various tissues, their genomic organization, and their homology to known genes. We have also identified an Alu insertion polymorphism in the intron of one of the transcripts. Overall, data on 13 novel transcripts and the human RGS8 gene (homologue of the rat RGS8 gene) are presented in this paper. Ten of the 13 novel transcripts are expressed in prostate tissue and represent positional candidates for HPC1.

Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation.

The mechanisms by which synchronized embryonic development to the blastocyst stage, preparation of the uterus for the receptive state, and reciprocal embryo-uterine interactions for implantation are coordinated are still unclear. We show in this study that preimplantation embryo development became asynchronous in mice that are deficient in brain-type (CB1) and/or spleen-type (CB2) cannabinoid receptor genes. Furthermore, whereas the levels of uterine anandamide (endocannabinoid) and blastocyst CB1 are coordinately down-regulated with the onset of uterine receptivity and blastocyst activation prior to implantation, these levels remained high in the nonreceptive uterus and in dormant blastocysts during delayed implantation and in pregnant, leukemia inhibitory factor (LIF)-deficient mice with implantation failure. These results suggest that a tight regulation of endocannabinoid signaling is important for synchronizing embryo development with uterine receptivity for implantation. Indeed this is consistent with our finding that while an experimentally induced, sustained level of an exogenously administered, natural cannabinoid inhibited implantation in wild-type mice, it failed to do so in CB1(-/-)/CB2(-/-) double mutant mice. The present study is clinically important because of the widely debated medicinal use of cannabinoids and their reported adverse effects on pregnancy.

Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor.

Cannabinoids have immunomodulatory as well as psychoactive effects. Because the central cannabinoid receptor (cannabinoid CB(1) receptor) is highly expressed in many neuronal tissues and the peripheral cannabinoid receptor (cannabinoid CB(2) receptor) is highly expressed in immune cells, it has been suggested that the central nervous system effects of cannabinoids are mediated by cannabinoid CB(1) receptors and that the immune effects are mediated by cannabinoid CB(2) receptors. To test this hypothesis, we have generated the first mouse strain with a targeted mutation in the cannabinoid CB(2) receptor gene. Binding studies using the highly specific synthetic cannabinoid receptor agonist (-)-cis-3-¿2-Hydroxy-4-(1, 1-dimethylheptyl)phenyl-trans-4-(3-hydroxypropyl)cyclohexanol (¿3HCP 55,940) revealed no residual cannabinoid binding sites in the spleen of the cannabinoid CB(2) receptor knockout mice, while binding in the central nervous system was unchanged. Cannabinoid CB(2) receptor knockout mice, which appear healthy, are fertile and care for their offspring. Fluorescence activated cell sorting (FACS) analysis showed no differences in immune cell populations between cannabinoid CB(2) receptor knockout and wildtype mice. We investigated the immunomodulatory effects of cannabinoids in cannabinoid CB(2) receptor deficient mice using a T cell co-stimulation assay. Delta(9)Tetrahydrocannabinol inhibits helper T cell activation through macrophages derived from wild type, but not from knockout mice, thus indicating that this effect is mediated by the cannabinoid CB(2) receptor. In contrast, central nervous system effects of cannabinoids were not altered in these mice. Our results suggest that cannabinoid CB(2) receptor-specific ligands may be clinically useful in the modulation of macrophage immune function while exhibiting no central nervous system activity. Furthermore, we conclude that the cannabinoid CB(2) receptor knockout mouse is a useful animal model in which to study the role of the cannabinoid system in immunoregulation.