Radiation therapy strategies for skull-base malignancies.

INTRODUCTION: The management of skull base malignancies continues to evolve with improvements in surgical technique, advances in radiation delivery and novel systemic agents. METHODS: In this review, we aim to discuss in detail the management of common skull base pathologies which typically require multimodality therapy, focusing on the radiotherapeutic aspects of care. RESULTS: Technological advances in the administration of radiation therapy have led to a wide variety of different treatment strategies for the treatment of skull base malignances, with outcomes summarized herein. CONCLUSION: Radiation treatment plays a key and critical role in the management of patients with skull base tumors. Recent advancements continue to improve the risk/benefit ratio for radiotherapy in this setting.

The use of mobile computed tomography in intensive care: regulatory compliance and radiation protection.

The use of mobile head computed tomography (CT) equipment in intensive care is of benefit to unstable patients with brain injury. However, ionising radiation in a ward environment presents difficulties due to the necessity to restrict the exposure to staff and members of the public according to regulation 8(1-2) of the Ionising Radiation Regulations 1999. The methodology for enabling the use of a mobile head CT unit in an open ward area is discussed and a practical solution given. This required the reduction in scatter doses through the installation of extra internal and external shielding, and a further reduction in annual scatter dose by restricting the use of the equipment based on a simulation of the annual ward workload.

Challenges to neurosurgery service delivery. Who moved my cheese?

The change programme in the National Health Service has moved the Acute Trusts providing neurosurgical services to very different ways of delivering healthcare. The process of reform has been supported by investment but the next few years will see far less additional money, and success and failure of services will be dependent upon the approach to those reforms. The 'payment by results' system of funding through tariff, the 'plurality of providers' policy of forcing commissioners to purchase activity from independent providers, the 'patient choice' process of encouraging patients to select treatment from a number of providers, and the '18-week wait' target of bringing down referral to treatment times are all major shifts in the way services are delivered and developed. The reforms have not been made with neurosurgery in mind, how will they affect the way this small specialty is delivered?

The evolutionary split of Pinaceae from other conifers: evidence from an intron loss and a multigene phylogeny.

The second intron in the mitochondrial gene nad1 was surveyed using PCR, DNA sequencing, or Southern hybridization in 323 species (313 genera, 212 families) of seed plants. The intron was absent in all 22 species (22 genera, 8 families) of non-Pinaceae conifers studied, in Welwitschia mirabilis, and in seven angiosperms. Whereas absence of the intron in seven angiosperms and Welwitschia is likely due to seven independent losses when evaluated against the recently published multigene phylogenies, the lack of the intron in all non-Pinaceae conifers can be best explained by a single loss. These data suggest that the non-Pinaceae conifers represent a monophyletic group. We also conducted a phylogenetic analysis of seed plants using a combined data set of the partial exon and intron sequences of nad1 generated from this study and published sequences of mitochondrial cox1 and small subunit (SSU) rDNA, chloroplast rbcL, and nuclear 18S rDNA. The results supported the split of conifers into two groups: Pinaceae and non-Pinaceae conifers. The Gnetales were sister to Pinaceae, in agreement with the conclusion from other recent molecular phylogenetic studies that refute the anthophyte hypothesis.

Mitochondrial gene transfer in pieces: fission of the ribosomal protein gene rpl2 and partial or complete gene transfer to the nucleus.

Mitochondrial genes are usually conserved in size in angiosperms. A notable exception is the rpl2 gene, which is considerably shorter in the eudicot Arabidopsis than in the monocot rice. Here, we show that a severely truncated mitochondrial rpl2 gene (termed 5' rpl2) was created by the formation of a premature stop codon early in eudicot evolution. This 5' rpl2 gene was subsequently lost many times from the mitochondrial DNAs of 179 core eudicots surveyed by Southern hybridization. The sequence corresponding to the 3' end of rice rpl2 (termed 3' rpl2) has been lost much more pervasively among the mitochondrial DNAs of core eudicots than has 5' rpl2. Furthermore, where still present in these mitochondrial genomes, 3' rpl2 always appears to be a pseudogene, and there is no evidence that 3' rpl2 was ever a functional mitochondrial gene. An intact and expressed 3' rpl2 gene was discovered in the nucleus of five diverse eudicots (tomato, cotton, Arabidopsis, soybean, and Medicago). In the first three of these species, 5' rpl2 is still present in the mitochondrion, unlike the two legumes, where both parts of rpl2 are present in the nucleus as separate genes. The full-length rpl2 gene has been transferred intact to the nucleus in maize. We propose that the 3' end of rpl2 was functionally transferred to the nucleus early in eudicot evolution, and that this event then permitted the nonsense mutation that gave rise to the mitochondrial 5' rpl2 gene. Once 5' rpl2 was established as a stand-alone mitochondrial gene, it was then lost, and was probably transferred to the nucleus many times. This complex history of gene fission and gene transfer has created four distinct types of rpl2 structures or compartmentalizations in angiosperms: (1) intact rpl2 gene in the mitochondrion, (2) intact gene in the nucleus, (3) split gene, 5' in the mitochondrion and 3' in the nucleus, and (4) split gene, both parts in the nucleus.

Lateral transfer at the gene and subgenic levels in the evolution of eukaryotic enolase.

Enolase genes from land plants and apicomplexa (intracellular parasites, including the malarial parasite, Plasmodium) share two short insertions. This observation has led to the suggestion that the apicomplexan enolase is the product of a lateral transfer event involving the algal endosymbiont from which the apicomplexan plastid is derived. We have examined enolases from a wide variety of algae, as well as ciliates (close relatives of apicomplexa), to determine whether lateral transfer can account for the origin of the apicomplexan enolase. We find that lateral gene transfer, likely occurring intracellularly between endosymbiont and host nucleus, does account for the evolution of cryptomonad and chlorarachniophyte algal enolases but fails to explain the apicomplexan enolase. This failure is because the phylogenetic distribution of the insertions--which we find in apicomplexa, ciliates, land plants, and charophyte green algae--directly conflicts with the phylogeny of the gene itself. Protein insertions have traditionally been treated as reliable markers of evolutionary events; however, these enolase insertions do not seem to reflect accurately the evolutionary history of the molecule. The lack of congruence between insertions and phylogeny could be because of the parallel loss of both insertions in two or more lineages, or what is more likely, because the insertions were transmitted between distantly related genes by lateral transfer and fine-scale recombination, resulting in a mosaic gene. This latter process would be difficult to detect without such insertions to act as markers, and such mosaic genes could blur the "tree of life" beyond the extent to which whole-gene lateral transfer is already known to confound evolutionary reconstruction.

Multiple losses and transfers to the nucleus of two mitochondrial succinate dehydrogenase genes during angiosperm evolution.

Unlike in animals, the functional transfer of mitochondrial genes to the nucleus is an ongoing process in plants. All but one of the previously reported transfers in angiosperms involve ribosomal protein genes. Here we report frequent transfer of two respiratory genes, sdh3 and sdh4 (encoding subunits 3 and 4 of succinate dehydrogenase), and we also show that these genes are present and expressed in the mitochondria of diverse angiosperms. Southern hybridization surveys reveal that sdh3 and sdh4 have been lost from the mitochondrion about 40 and 19 times, respectively, among the 280 angiosperm genera examined. Transferred, functional copies of sdh3 and sdh4 were characterized from the nucleus in four and three angiosperm families, respectively. The mitochondrial targeting presequences of two sdh3 genes are derived from preexisting genes for anciently transferred mitochondrial proteins. On the basis of the unique presequences of the nuclear genes and the recent mitochondrial gene losses, we infer that each of the seven nuclear sdh3 and sdh4 genes was derived from a separate transfer to the nucleus. These results strengthen the hypothesis that angiosperms are experiencing a recent evolutionary surge of mitochondrial gene transfer to the nucleus and reveal that this surge includes certain respiratory genes in addition to ribosomal protein genes.

Prospective study of swallowing function in patients with cervical dystonia undergoing selective peripheral denervation.

OBJECTIVE: To characterise swallowing function in patients with cervical dystonia with botulinum toxin treatment failure, before and after selective peripheral denervation surgery. METHODS: Twelve patients with cervical dystonia had a thorough examination including standardised assessment for cervical dystonia, scoring of subjective dysphagia, and videofluoroscopic swallow. Videofluoroscopy was scored by consensus opinion between a speech and language therapist and an independent blinded radiologist using a validated scoring system. RESULTS: Seven patients with cervical dystonia experienced no subjective dysphagia either before or after surgery, although in all these patients there was objective videofluoroscopic evidence of underlying mild to moderate oropharyngeal dysphagia preoperatively and postoperatively. The most common finding was delayed initiation of swallow. Three other patients, also without subjective dysphagia before surgery, developed postoperative dysphagia. In these patients, videofluoroscopy showed a delayed swallow reflex before surgery, which was worse postoperatively in two. The remaining two patients had mild subjective dysphagia before surgery that improved postoperatively in one and deteriorated in the other. In the first, videofluoroscopy was normal preoperatively and postoperatively, and in the second, oral bolus preparation was moderately abnormal preoperatively and swallow initiation was delayed postoperatively. Mean subjective dysphagia scores did not change significantly. Apart from a significant improvement of tongue base retraction, videofluoroscopic scores were not significantly different after surgery. Postoperatively there was significant improvement of overall cervical dystonia severity and abnormal head rotation in the group as a whole. There was no correlation between age, duration of symptoms of cervical dystonia, preoperative or postoperative cervical dystonia severity, subjective dysphagia scores, or videofluoroscopic scores. However, in the five patients with persisting anterior sagittal head shift as part of the torticollis, tongue base retraction was less likely to improve after surgery compared with those without head shift. CONCLUSION: Surgical denervation of dystonic neck muscles, leading to improved neck posture, can also improve tongue base retraction, which is a key component of normal bolus propagation. However, delayed swallow initiation, a common feature in patients with cervical dystonia, can be further compromised by surgery, leading to subjective dysphagia. In general, selective peripheral denervation seems to be a safe procedure with no major compromise of swallowing function.

Polymyography combined with time-locked video recording (video EMG) for presurgical assessment of patients with cervical dystonia.

We assessed 26 patients with cervical dystonia, in whom botulinum toxin (BT) injections had failed, before selective peripheral denervation. We decided to base the decision which muscle should be denervated on both clinical information and EMG data and focussed on the following features: activity at onset or during 'dystonic spasms' (according to the concept of the 'leading' dystonic muscle), paradoxical activity during voluntary head movements causing restriction of head movements opposite the side of head turn or tilt and activity when symptoms deteriorated during walking. To identify these muscles we developed a new recording system that integrates simultaneous video-taping and polymyography (video EMG) by means of a digital counter, driven by the recording software (resolution 0.1 s), that was fixed in view of the video camera. This system time-locked clinical signs with relevant EMG activity thus allowing demonstration of the above features. These were found in 68% of dystonic muscles with each of them being present in approximately 40%. Video EMG allows an integrated approach to identify overactive neck muscles in patients with cervical dystonia taking into account both relevant clinical findings and EMG data.

Prospective study of selective peripheral denervation for botulinum-toxin resistant patients with cervical dystonia.

We have carried out a prospective study of selective peripheral denervation (SPD) in cervical dystonia (CD) patients with primary or secondary botulinum toxin (BT) treatment failure using independent standardized assessment. Patients referred for surgery had a standardized clinical examination, neck muscle EMG, videofluoroscopic swallow and CT of the cervical spine, and were selected for surgery on the basis of the results of these investigations. CD severity, disability and pain were assessed preoperatively and at 3, 6, 9, 12 and 18 months postoperatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Severity of head tremor and dysphagia were scored using established rating scales. Additionally, psychosocial function was assessed in a representative subsample of patients (n = 12) using several established questionnaires. Of the 62 patients who were assessed, 22 (35.5%) were not offered surgery, most commonly because of widespread dystonia. Of the remaining 40 patients, 37 have so far had surgery, 31 of whom have been followed up for at least 1 year, and 15 for 18 months after surgery (mean follow-up duration 16.7 months). Using the TWSTRS global outcome score, 68% of patients derived functionally relevant improvement at 12 months after surgery. In the entire operated group, total TWSTRS scores were reduced by 30% at 6 and 12 months after surgery (P < 0.0001). The subscores for severity, disability and pain were reduced by 20, 30 and 40%, respectively, at 6 months (P < or = 0.01) and 20, 40 and 30%, respectively, at 12 months (P < 0.01). Pain increased over time, which appeared to result from muscle reinnervation. TWSTRS scores were not significantly improved in the six patients with primary BT treatment failure. Head tremor did not change. There was a significant improvement of body concept, perceived disfigurement, stigma, and quality of life in the 12 patients whose psychosocial function was assessed. Preoperative disability and restriction of head movement were negatively correlated and the initial response to BT treatment positively correlated with global outcome score. Spread or deterioration of dystonia elsewhere in the body occurred in three patients, with unpleasant sensory symptoms in denervated posterior cervical segments occurring in 14. Ten patients developed mild to moderate dysphagia, and two developed severe dysphagia. We conclude that SPD is an effective treatment for patients with secondary, but probably not for those with primary, BT treatment failure. Reinnervation is not infrequent and can compromise outcome. Postoperative morbidity is low, but there is a risk of dysphagia.

Many parallel losses of infA from chloroplast DNA during angiosperm evolution with multiple independent transfers to the nucleus.

We used DNA sequencing and gel blot surveys to assess the integrity of the chloroplast gene infA, which codes for translation initiation factor 1, in >300 diverse angiosperms. Whereas most angiosperms appear to contain an intact chloroplast infA gene, the gene has repeatedly become defunct in approximately 24 separate lineages of angiosperms, including almost all rosid species. In four species in which chloroplast infA is defunct, transferred and expressed copies of the gene were found in the nucleus, complete with putative chloroplast transit peptide sequences. The transit peptide sequences of the nuclear infA genes from soybean and Arabidopsis were shown to be functional by their ability to target green fluorescent protein to chloroplasts in vivo. Phylogenetic analysis of infA sequences and assessment of transit peptide homology indicate that the four nuclear infA genes are probably derived from four independent gene transfers from chloroplast to nuclear DNA during angiosperm evolution. Considering this and the many separate losses of infA from chloroplast DNA, the gene has probably been transferred many more times, making infA by far the most mobile chloroplast gene known in plants.

Abnormal interaction between vestibular and voluntary head control in patients with spasmodic torticollis.

The functional status of vestibulo-collic reflexes in the sternocleidomastoid (SCM) muscles was investigated in 24 patients with spasmodic torticollis using small, abrupt 'drops' of the head. None had been treated with botulinum toxin injections during at least 4 months preceding the study. Eight of the patients, four of whom had been studied before surgery, were also studied after selective peripheral denervation of neck muscles. The reflex was of normal latency and duration in the 'passive drop' condition, in which subjects were instructed not to oppose the fall of the head. To study voluntary interaction with the reflex response, subjects were then asked to flex the neck as quickly as possible after onset of the head drop ('active drop'). In this condition, voluntary responses in patients were delayed, smaller and less effective in counteracting the head fall than in normal subjects. The same abnormalities were also found in patients after surgery when the head posture was improved. Somatosensory/auditory voluntary reaction times in SCM were normal, as was the latency of the startle reflex. We conclude that voluntary interaction with the vestibulo-collic reflex is disrupted in patients with spasmodic torticollis, a finding which corroborates the patients' aggravation of their symptoms by head or body perturbations. Lack of effective interaction between two major systems controlling head position may contribute to torticollis.

Repeated, recent and diverse transfers of a mitochondrial gene to the nucleus in flowering plants.

A central component of the endosymbiotic theory for the bacterial origin of the mitochondrion is that many of its genes were transferred to the nucleus. Most of this transfer occurred early in mitochondrial evolution; functional transfer of mitochondrial genes has ceased in animals. Although mitochondrial gene transfer continues to occur in plants, no comprehensive study of the frequency and timing of transfers during plant evolution has been conducted. Here we report frequent loss (26 times) and transfer to the nucleus of the mitochondrial gene rps10 among 277 diverse angiosperms. Characterization of nuclear rps10 genes from 16 out of 26 loss lineages implies that many independent, RNA-mediated rps10 transfers occurred during recent angiosperm evolution; each of the genes may represent a separate functional gene transfer. Thus, rps10 has been transferred to the nucleus at a surprisingly high rate during angiosperm evolution. The structures of several nuclear rps10 genes reveal diverse mechanisms by which transferred genes become activated, including parasitism of pre-existing nuclear genes for mitochondrial or cytoplasmic proteins, and activation without gain of a mitochondrial targeting sequence.

Multigene phylogeny of land plants with special reference to bryophytes and the earliest land plants.

A widely held view of land plant relationships places liverworts as the first branch of the land plant tree, whereas some molecular analyses and a cladistic study of morphological characters indicate that hornworts are the earliest land plants. To help resolve this conflict, we used parsimony and likelihood methods to analyze a 6, 095-character data set composed of four genes (chloroplast rbcL and small-subunit rDNA from all three plant genomes) from all major land plant lineages. In all analyses, significant support was obtained for the monophyly of vascular plants, lycophytes, ferns (including PSILOTUM: and EQUISETUM:), seed plants, and angiosperms. Relationships among the three bryophyte lineages were unresolved in parsimony analyses in which all positions were included and weighted equally. However, in parsimony and likelihood analyses in which rbcL third-codon-position transitions were either excluded or downweighted (due to apparent saturation), hornworts were placed as sister to all other land plants, with mosses and liverworts jointly forming the second deepest lineage. Decay analyses and Kishino-Hasegawa tests of the third-position-excluded data set showed significant support for the hornwort-basal topology over several alternative topologies, including the commonly cited liverwort-basal topology. Among the four genes used, mitochondrial small-subunit rDNA showed the lowest homoplasy and alone recovered essentially the same topology as the multigene tree. This molecular phylogeny presents new opportunities to assess paleontological evidence and morphological innovations that occurred during the early evolution of terrestrial plants.

Dynamic evolution of plant mitochondrial genomes: mobile genes and introns and highly variable mutation rates.

We summarize our recent studies showing that angiosperm mitochondrial (mt) genomes have experienced remarkably high rates of gene loss and concomitant transfer to the nucleus and of intron acquisition by horizontal transfer. Moreover, we find substantial lineage-specific variation in rates of these structural mutations and also point mutations. These findings mostly arise from a Southern blot survey of gene and intron distribution in 281 diverse angiosperms. These blots reveal numerous losses of mt ribosomal protein genes but, with one exception, only rare loss of respiratory genes. Some lineages of angiosperms have kept all of their mt ribosomal protein genes whereas others have lost most of them. These many losses appear to reflect remarkably high (and variable) rates of functional transfer of mt ribosomal protein genes to the nucleus in angiosperms. The recent transfer of cox2 to the nucleus in legumes provides both an example of interorganellar gene transfer in action and a starting point for discussion of the roles of mechanistic and selective forces in determining the distribution of genetic labor between organellar and nuclear genomes. Plant mt genomes also acquire sequences by horizontal transfer. A striking example of this is a homing group I intron in the mt cox1 gene. This extraordinarily invasive mobile element has probably been acquired over 1,000 times separately during angiosperm evolution via a recent wave of cross-species horizontal transfers. Finally, whereas all previously examined angiosperm mtDNAs have low rates of synonymous substitutions, mtDNAs of two distantly related angiosperms have highly accelerated substitution rates.

Precise cannulation of the foramen ovale in trigeminal neuralgia complicating osteogenesis imperfecta with basilar invagination: technical case report.

OBJECTIVE AND IMPORTANCE: Trigeminal neuralgia is a rare feature of basilar invagination, which is itself a complication of osteochondrodysplastic disorders. Microvascular decompression is an unattractive option in medically refractory cases. The conventional percutaneous approach to the trigeminal ganglion is anatomically impossible because the foramen ovale points inferiorly and posteromedially. We report a new technique for image-guided trigeminal injection in a patient with basilar invagination complicating osteogenesis imperfecta. CLINICAL PRESENTATION: A 26-year-old woman with osteogenesis imperfecta presented with a 3-year history of typical left maxillary division trigeminal neuralgia, which was poorly controlled by carbamazepine at the maximum tolerated dose. She had obvious cranial deformities, left optic atrophy, delayed left eye closure, tongue atrophy, but normal facial sensation and corneal reflexes. A computed tomographic scan and magnetic resonance imaging confirmed severe basilar invagination. TECHNIQUE: Frameless stereotactic glycerol injection of the left trigeminal ganglion was performed under general anesthesia using the infrared-based EasyGuide Neuro system (Philips Medical Systems, Best, The Netherlands) with magnetic resonance imaging and computed tomographic registration. The displaced and distorted left foramen ovale was cannulated via a true frameless stereotactic method with the trajectory determined by virtual pointer elongation. The needle placement was confirmed with injection of contrast medium into the trigeminal cistern. The path needed to enter the foramen traversed the right cheek, soft palate, and left tonsil. The patient went home pain-free with a preserved corneal reflex and no complications. CONCLUSION: Frameless stereotaxy allows customization to individual patient anatomy and may be adapted to a variety of percutaneous procedures used in areas where the anatomy is complex.

Seed plant phylogeny inferred from all three plant genomes: monophyly of extant gymnosperms and origin of Gnetales from conifers.

Phylogenetic relationships among the five groups of extant seed plants are presently quite unclear. For example, morphological studies consistently identify the Gnetales as the extant sister group to angiosperms (the so-called "anthophyte" hypothesis), whereas a number of molecular studies recover gymnosperm monophyly, and few agree with the morphology-based placement of Gnetales. To better resolve these and other unsettled issues, we have generated a new molecular data set of mitochondrial small subunit rRNA sequences, and have analyzed these data together with comparable data sets for the nuclear small subunit rRNA gene and the chloroplast rbcL gene. All nuclear analyses strongly ally Gnetales with a monophyletic conifers, whereas all mitochondrial analyses and those chloroplast analyses that take into account saturation of third-codon position transitions actually place Gnetales within conifers, as the sister group to the Pinaceae. Combined analyses of all three genes strongly support this latter relationship, which to our knowledge has never been suggested before. The combined analyses also strongly support monophyly of extant gymnosperms, with cycads identified as the basal-most group of gymnosperms, Ginkgo as the next basal, and all conifers except for Pinaceae as sister to the Gnetales + Pinaceae clade. According to these findings, the Gnetales may be viewed as extremely divergent conifers, and the many morphological similarities between angiosperms and Gnetales (e.g., double fertilization and flower-like reproductive structures) arose independently.