A homozygous FKRP start codon mutation is associated with Walker–Warburg syndrome,the severe end of the clinical spectrum

van Reeuwijk J, Olderode‐Berends MJW, van den Elzen C, Brouwer OF, Roscioli T, van Pampus MG, Scheffer H, Brunner HG, van Bokhoven H, Hol FA. A homozygous FKRP start codon mutation is associated with Walker–Warburg syndrome, the severe end of the clinical spectrum. Dystroglycanopathies are a heterogeneous group of disorders caused by defects in the glycosylation pathway of α‐dystroglycan. The clinical spectrum ranges from severe congenital muscular dystrophy with structural brain and eye involvement to a relatively mild adult onset limb‐girdle muscular dystrophy without brain abnormalities and normal intelligence. Mutations have been identified in one of six putative or demonstrated glycosyltransferases. Many different FKRP mutations have been identified, which cover the complete clinical spectrum of dystroglycanopathies. In contrast to the other known genes involved in these disorders, genotype–phenotype correlations are not obvious for FKRP mutations. To date, no homozygous or compound heterozygous null mutations have been identified in FKRP, suggesting that null mutations in FKRP could result in embryonic lethality. We report a family with two siblings carrying a homozygous mutation in the start codon of FKRP that is likely to result in a loss of functional FKRP protein. The clinical phenotype of the patients was consistent with Walker–Warburg syndrome, the most severe disorder in the disease spectrum of dystroglycanopathies.     

Structural relatedness between the 18S rRNA genes and the formyl peptide receptor genes: new insights into the phylogenesis of immune receptors

In this study the authors examined the sequences of the ribosomal 18S rRNA of Drosophila and man and 16 mRNA sequences coding for different members of the family of the mammalian formyl peptide receptors (FPRs). The positions in the sequences of all >or=7-base oligonucleotide identities occurring in at least one of the 18S rRNAs and one of the FPR mRNAs were recorded. On the basis of the positional data, the Drosophila 18S-FPR and human 18S-FPR distances (in nucleotides) were determined for each identity. Then the actual frequency distribution of the distances (grouped into 200-unit classes) was derived. The theoretical frequency distribution of distances was also calculated under the assumption of non-relatedness between the 18S and FPR sequences. Comparison between the theoretical and the actual distributions showed that at class -500 (range from - 400 to - 600) of the 18S-FPR values the actual frequency was significantly (p < 0.01) higher than the theoretical frequency, in both Drosophila and man, suggesting that the second section of the FPR genes (approximately from nucleotide 400 to the end of sequence) may be structurally related to the first section of the ribosomal 18S genes (approximately nucelotides 1-650). The authors advance the hypothesis that the two families of genes may have used common ancestral raw genetic materials in the building of the extant sequences.     

Foreign body giant cell reaction to polytetrafluoroethylene used as interposition material in scaphoid-trapezium arthroplasty

We present the case of a 54-year-old woman who presented with a one and a half-year history of persistent pain at the base of her right thumb. A scaphoid-trapezium interposition arthroplasty with polytetrafluoroethylene was carried out in an effort to improve function and decrease the patient's persistent pain. Approximately 7 years after surgery, she began to complain of increasing pain and radiographs showed extensive osteolytic changes, consistent with a foreign body giant cell reaction.     

Dual effect of nitric oxide on uterine prostaglandin synthesis in a murine model of preterm labour

BACKGROUND AND PURPOSE

Maternal infections are one of the main causes of adverse developmental outcomes including embryonic resorption and preterm labour. In this study a mouse model of inflammation-associated preterm delivery was developed, and used to study the relationship between nitric oxide (NO) and prostaglandins (PGs).

EXPERIMENTAL APPROACH

The murine model of preterm labour was achieved by assaying different doses of bacterial lipopolysaccharides (LPS). Once established, it was used to analyse uterine levels of prostaglandins E₂ and F_2α (by radioimmunoassay), cyclooxygenases (COX) and NOS proteins (by Western blot) and NO synthase (NOS) activity. Effects of inhibitors of COX and NOS on LPS-induced preterm labour were also studied. In vitro assays with a nitric oxide donor (SNAP) were performed to analyse the modulation of prostaglandin production by NO.

KEY RESULTS

Lipopolysaccharide increased uterine NO and PG synthesis and induced preterm delivery. Co-administration of meloxicam, a cyclooxygenase-2 inhibitor, or aminoguanidine, an inducible NOS inhibitor, prevented LPS-induced preterm delivery and blocked the increase in PGs and NO. Notably, the levels of NO were found to determine its effect on PG synthesis; low concentrations of NO reduced PG synthesis whereas high concentrations augmented them.

CONCLUSIONS AND IMPLICATIONS

An infection-associated model of preterm labour showed that preterm delivery can be prevented by decreasing PG or NO production. NO was found to have a dual effect on PG synthesis depending on its concentration. These data contribute to the understanding of the interaction between NO and PGs in pregnancy and parturition, and could help to improve neonatal outcomes.     

Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist

Background and purpose:

Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being Δ⁹-tetrahydrocannabinol, cannabidiol and Δ⁹-tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor.

Experimental approach:

The [³⁵S]GTPγS binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [³H]CP55940 from mouse CB₁ and human CB₂ cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.

Key results:

In the brain membrane experiments, cannabigerol behaved as a potent α₂-adrenoceptor agonist (EC₅₀= 0.2 nM) and antagonized the 5-HT_1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K_B= 51.9 nM). At 10 µM, it also behaved as a CB₁ receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be α₂-adrenoceptor-mediated (EC₅₀= 72.8 nM) and displayed significant affinity for mouse CB₁ and human CB₂ receptors.

Conclusions and implications:

This investigation has provided the first evidence that cannabigerol can activate α₂-adrenoceptors, bind to cannabinoid CB₁ and CB₂ receptors and block CB₁ and 5-HT_1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [³⁵S]GTPγS binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain.     

Advances in imaging of new targets for pharmacological intervention in stroke: real-time tracking of T-cells in the ischaemic brain

Background and purpose:

T-cells may play a role in the evolution of ischaemic damage and repair, but the ability to image these cells in the living brain after a stroke has been limited. We aim to extend the technique of real-time in situ brain imaging of T-cells, previously shown in models of immunological diseases, to models of experimental stroke.

Experimental approach:

Male C57BL6 mice (6–8 weeks) (n= 3) received a total of 2–5 × 10⁶ carboxyfluorescein diacetate succinimidyl ester (CFSE)-labelled lymphocytes from donor C57BL6 mice via i.v. injection by adoptive transfer. Twenty-four hours later, recipient mice underwent permanent left distal middle cerebral artery occlusion (MCAO) by electrocoagulation or by sham surgery under isoflurane anaesthesia. Female hCD2-green fluorescent protein (GFP) transgenic mice that exhibit GFP-labelled T-cells underwent MCAO. At 24 or 48 h post-MCAO, a sagittal brain slice (1500 µm thick) containing cortical branches of the occluded middle cerebral artery (MCA) was dissected and used for multiphoton laser scanning microscopy (MPLSM).

Key results:

Our results provide direct observations for the first time of dynamic T-cell behaviour in living brain tissue in real time and herein proved the feasibility of MPLSM for ex vivo live imaging of immune response after experimental stroke.

Conclusions and Implications:

It is hoped that these advances in the imaging of immune cells will provide information that can be harnessed to a therapeutic advantage.This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476-5381.2010.00685.x     

Esophageal injuries: spectrum of multidetector row CT findings

BACKGROUND: Aim of this study is to illustrate the multidetector row computed tomographic findings related to oesophageal injuries and their significance for therapeutic decisions. METHOD: From April 2002 to April 2005 we studied 16 patients with suspected oesophageal injury. Ten patients underwent standard chest radiograph, while five patients with suspected foreign body ingestion were submitted to cervical plain film and gastrografin swallow study. All 16 patients underwent multidetector row CT examination. RESULTS: In six patients with cervical, thoracic and abdominal trauma, CT showed the presence of thoracic traumatic lesions and findings suggestive of perforation of the oesophagus. In five patients with foreign body ingestion cervical radiography was positive in only one case, while CT showed the presence of a foreign body in all cases. In three patients with post-intubation complications, CT showed the presence of perioesophageal fluid collection containing small gas bubbles in two cases and an oesophageal-aortic fistula in one case. In the remaining two patients with suspected spontaneous oesophageal perforation, CT demonstrated an oesophageal wall oedema and thickening in one case, and oesophageal fluid distension with perioesophageal small bubbles gas and fluid in the second case. CONCLUSION: Oesophageal injuries, when complicated with perforation, constitute a life-threatening condition. Knowledge of the CT signs of oesophageal injuries has important implications for the role of imaging at the time of initial diagnosis.