Non-invasive radiological investigation for oculomotor palsy.

An application of computed tomography (CT) is described in which multiplanar high resolution images of the terminal carotid and basilar arteries are obtained. This has been applied in a series of 32 patients with IIIrd nerve palsy in whom the underlying pathology was thought to be a posterior communicating artery aneurysm. The results of the CT were compared with conventional angiography. Seventeen aneurysms were detected in 13 patients by CT and all were confirmed by angiography. Vessels considered to be normal on CT were confirmed to be normal by angiography. This CT technique is a simple non invasive first line investigation for IIIrd nerve palsy with the ability to exclude or predict an aneurysm.     

hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation–contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation–contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.The expression of more than 95% of human genes is affected by alternative pre-mRNA splicing (AS) (1, 2). Differentially spliced isoforms play distinct roles in a temporally and spatially specific manner (3), and mutations that lead to aberrant splicing are the cause of many human genetic diseases (4). RNA-binding proteins (RBPs) play a central role in the regulation of alternative splicing during development and disease. They function primarily by positively or negatively regulating splice-site recognition by the spliceosome (1). Many RBPs are expressed in specific tissues, and AS is regulated by the combinatorial activities of these factors on specific pre-mRNAs through their interactions with distinct regulatory sequences in pre-mRNA that function as splicing enhancers or silencers (5).The developing heart is one of the best studied systems where splicing changes occur during normal development, and mutations affecting specific splicing outcomes contribute to cardiomyopathy (6, 7). Although these mutations can either disrupt splicing elements or affect the expression of specific splicing factors, the latter mechanism is clearly responsible for the distinct splicing profiles at different developmental stages. For example, the dynamics of alternative splicing during postnatal heart development correlate with expression changes of many RBPs, including CUG-BP, Elav-like family member 1 (CELF1), Muscleblind-like 1 (MBNL1), and FOX proteins (8). Detailed biochemical studies have elucidated the mechanisms by which these splicing factors regulate splicing in a position- and context-dependent manner (9, 10). The function of other RBPs during heart development has also been studied. For example, two of the muscle-specific splicing factors, RBM20 and RBM24, play distinct roles in splicing regulation. RBM20 mainly acts as a splicing repressor, as its absence leads to multiple exon inclusion events in the heart. For example, the Titin gene is one of the major targets of RBM20 (11, 12). On the other hand, loss of RBM24 expression gives rise to many exon skipping events (13), implicating RBM24 as a splicing activator. Strikingly, there is little overlap between RBM20 and RBM24 splicing targets, suggesting that RBM20 and RBM24 are involved in regulating splicing of distinct groups of pre-mRNAs and there is little cross-talk between these two splicing factors.Distinct splicing activities have also been ascribed to general splicing factors (1). There are two major types of ubiquitously expressed RBPs: the heterogeneous nuclear ribonucleoproteins (hnRNPs) and serine/arginine (SR)-rich proteins. hnRNPs and SR proteins are generally believed to play opposite roles in splicing: SR proteins promote the inclusion of exons during splicing, whereas hnRNP proteins repress inclusion (1). The function of certain SR proteins has been studied in the mouse heart through the conditional knockout approach. Srsf1 deletion in the heart leads to lethal dilated cardiomyopathy (DCM) (death occurs 6–8 wk after birth) (14). SRSF1 is required for the cardiac-specific splicing of Cypher (also called Ldb3) pre-mRNA, and the regulation of alternative splicing of calcium/calmodulin-dependent protein kinase II delta (Camk2d) and cardiac Troponin T (cTnT) during heart development. In particular, the persistent splicing of a neuronal isoform of Camk2d and its ability to enhance excitation and contraction coupling (ECC) activity in Srsf1 mutant cardiomyocytes have been proposed as a possible cause of the phenotype in mutant mice (14). Ablation of another SR protein, SRSF10 (SRp38), from the mouse also leads to heart defects (15). SRSF10 has been shown to regulate the splicing of Triadin, an important component of ECC machinery (15). Interestingly, conditional deletion of Srsf2 from the heart leads to DCM with little splicing misregulation but instead affects the expression of the calcium channel Ryr2 (16). It is striking that these SR proteins affect ECC activity in the heart by directly regulating the expression/splicing of distinct players in this machinery. Because these studies were conducted before the advent of next-generation RNA sequencing, only a few splicing targets specifically regulated by these SR proteins were identified. A more comprehensive study of the effects of deleting the genes encoding these proteins from the heart on the splicing program has not been reported.In contrast to SR proteins, specific functions of hnRNP proteins in cardiac pre-mRNA splicing have not been determined. In this report, we selectively inactivated the expression of one of the most abundant hnRNP proteins—hnRNP U—in the heart. We found that Hnrnpu mutant mice develop a lethal DCM phenotype, with death occurring around 2 wk after birth. There are multiple cardiac defects in mutant hearts accompanied by many splicing alterations. Some of these splicing targets are commonly regulated by hnRNP U and other SR and RBM proteins. We also identified many hnRNP U-specific splicing targets in the heart, including an ECC component Junctin. The protein product of the alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site in Hnrnpu mutant cells and could contribute to abnormal cardiac function. Our study also enables comparisons of the roles of different splicing factors in heart development and function.     

Spontaneous hemorrhagic Descemet membrane detachment causing pupillary block

Purpose. To present a unique case of a 65-year-old man using warfarin who presented with acute unilateral loss of vision due to hemorrhagic Descemet membrane detachment (DMD) with pupillary block and elevated intraocular pressure and its subsequent treatment and challenges. Method. Case report. Results. Clinical examination showed a visual acuity of finger counting, central DMD with near contact to the iris and premembrane hemorrhage, an intraocular pressure (IOP) of 19 mmHg, and normal pupillary reaction. An International Normalized Ratio (INR) of 4.9 was treated with dose reduction and vitamin K. Twelve hours later the patient re-presented with an acute increase in pain and an IOP of 78 mmHg with pupillary block and iris bombé. YAG-laser membranotomy, anterior chamber paracentesis, and maximal topical and systemic therapy were unsuccessful in reducing the IOP. Surgical management, including irrigation and aspiration of blood, led to a normalization of the IOP. Descemet stripping automated endothelial keratoplasty (DSAEK) resulted in a visual acuity of 0.3. Deep stromal/pre-Descemet membrane neovascularization was found bilaterally, suspicious for a previous interstitial keratitis. Conclusions. The previously unreported complication of pupillary block following a pre-Descemet membrane hemorrhage was treated successfully for the first reported time, in a 2-step DSAEK. This indicates that DSAEK could be considered as a treatment option for DMD, especially in traumatic circumstances.     

Central nervous system lesions in Malawian children: identifying the treatable

In Malawi, children with central nervous system (CNS) tumours are seldom able to be treated with curative intent. A study was undertaken of 29 children who underwent CNS MRI during a two year period. A combination of neoplastic and non-neoplastic diagnoses were noted, seven of which were revised on review. As a result an effective system has been set up for remote urgent review to guide prognosis and treatment. The opinion of a paediatric neuro-radiologist greatly assists in differentiating infectious and non infectious causes of CNS lesions and can enable the local team to effectively triage patients.     

Reduced bone density in patients with inflammatory bowel disease.

BACKGROUND: Reduced bone mineral density in patients with inflammatory bowel disease is thought to be due to disturbances in calcium homeostasis or the effects of corticosteroid treatment. AIMS: To assess the prevalence and mechanism of reduced bone mineral density in 79 patients with inflammatory bowel disease (44 with Crohn's disease, 35 with ulcerative colitis) who did not have significant risk factors for low bone densities. METHODS: Dual x ray absorptiometry was used to measure bone mineral density and serum and urinary markers of osteoblast (alkaline phosphatase, procollagen 1 carboxy terminal peptide and osteocalcin) and osteoclast (pyridinoline, deoxypyridinoline, and type 1 collagen carboxy terminal peptide) activities to assess bone turnover. RESULTS: There was a high prevalence of low bone mineral density (prevalence of T scores < -1.0 from 51%-77%; T scores < -2.5 (osteoporosis) from 17%-28%) with hips being more often affected than vertebrae (p < 0.001). Reduced bone mineral density did not relate to concurrent or past corticosteroid intake, or type, site, or severity of disease. Whereas calcium homeostasis was normal, bone markers showed increased bone resorption without a compensatory increase in bone formation. CONCLUSIONS: The greater prevalence of reduced hip bone mineral density, as opposed to vertebral, mineral density and the pattern of a selective increase in bone resorption contrasts with that found in other known causes of metabolic bone disease.     

A randomised controlled trial of a smoking cessation intervention delivered by dental hygienists: a feasibility study

Background  

Tobacco use continues to be a global public health problem. Helping patients to quit is part of the preventive role of all health professionals. There is now increasing interest in the role that the dental team can play in helping their patients to quit smoking. The aim of this study was to determine the feasibility of undertaking a randomised controlled smoking cessation intervention, utilising dental hygienists to deliver tobacco cessation advice to a cohort of periodontal patients.