The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death.

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inherit wtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy spores.

Meiotic drivers are genes that break the normal rules of inheritance. Usually, a gene has a 50% chance of passing on to the next generation. Meiotic drivers force their way into the next generation by poisoning the gametes (the sex cells that combine to form a zygote) that do not carry them. Harnessing the power of genetic drivers could allow scientists to spread beneficial genes across populations. One group of meiotic drivers found in fission yeast is called the 'with transposon fission yeast', or 'wtf' gene family. The wtf drivers act during the production of spores, which are the fission yeast equivalent of sperm, and they encode both a poison that can destroy the spores and its antidote. The poison spreads through the sac holding the spores, and can affect all of them, while the antidote only protects the spores that make it. This means that the spores carrying the wtf genes survive, while the rest of the spores are killed. To understand whether it is possible to use the wtf meiotic drivers to spread other genes, perhaps outside of fission yeast, scientists must first establish exactly how the proteins coded for by genes behave. To do this, Nuckolls et al. examined a member of the wtf family called wtf4. Attaching a fluorescent label to the poison and antidote proteins produced by wtf4 made it possible to see what they do. This revealed that the poison clumps, forming toxic aggregates that damage yeast spores. The antidote works by mopping up these aggregates and moving them to the cell's main storage compartment, called the vacuole. Mutations that disrupted the ability of the antidote to interact with the poison or its ability to move the poison into storage stopped the antidote from working. Nuckolls et al. also showed that if genetic engineering was used to introduce wtf4 into a distantly related species of budding yeast the effects of this meiotic driver were the same. This suggests that the wtf genes may be good candidates for future genetic engineering experiments. Engineered systems known as 'gene drives' could spread beneficial genetic traits through populations. This could include disease-resistance genes in crops, or disease-preventing genes in mosquitoes. The wtf genes are small and work independently of other genes, making them promising candidates for this type of system. These experiments also suggest that the wtf genes could be useful for understanding why clumps of proteins are toxic to cells. Future work could explore why clumps of wtf poison kill spores, while clumps of poison plus antidote do not. This could aid research into human ailments caused by protein clumps, such as Huntington's or Alzheimer's disease.

3D-printed Titanium Prosthetic Reconstruction of the C2 Vertebra: Techniques and Outcomes of Three Consecutive Cases.

STUDY DESIGN: Three patients were treated at our center with patient-specific three-dimensional (3D)-printed titanium prostheses for the reconstruction of structurally compromised C2 vertebrae. OBJECTIVE: To describe our surgical and device design approach to these clinical scenarios and evaluate their outcomes. SUMMARY OF BACKGROUND DATA: There are a limited but increasing number of case reports and series describing the use of 3D-printed prostheses for high cervical surgery. METHODS: We have collated and reviewed three cases using patient-specific 3D-printed prostheses. RESULTS: We report two cases arising from neoplastic destruction; one resulting from metastatic medullary thyroid carcinoma, and the other from multiple myeloma. We additionally describe a case of C2 compromise as a complication of rheumatoid arthritis. All patients included in this report achieved successful surgical outcomes and symptom relief without significant complication. Clinical and radiological follow-up has demonstrated good outcomes in all cases up to 14-months postprocedure. CONCLUSIONS: These cases describe successful use of custom 3D-printed prostheses for reconstruction of the anterior vertebral column through C2, and add to the emerging body of literature detailing the use of custom prostheses for complex spinal surgery. LEVEL OF EVIDENCE: 4.

Attempted use of PACE for riboswitch discovery generates three new translational theophylline riboswitch side products.

OBJECTIVE: The purpose of this project was to use an in vivo method to discover riboswitches that are activated by new ligands. We employed phage-assisted continuous evolution (PACE) to evolve new riboswitches in vivo. We started with one translational riboswitch and one transcriptional riboswitch, both of which were activated by theophylline. We used xanthine as the new target ligand during positive selection followed by negative selection using theophylline. The goal was to generate very large M13 phage populations that contained unknown mutations, some of which would result in new aptamer specificity. We discovered side products of three new theophylline translational riboswitches with different levels of protein production. RESULTS: We used next generation sequencing to identify M13 phage that carried riboswitch mutations. We cloned and characterized the most abundant riboswitch mutants and discovered three variants that produce different levels of translational output while retaining their theophylline specificity. Although we were unable to demonstrate evolution of new riboswitch ligand specificity using PACE, we recommend careful design of recombinant M13 phage to avoid evolution of "cheaters" that short circuit the intended selection pressure.

Spontaneous peritoneal catheter knot formation: A rare cause of ventriculoperitoneal shunt malfunction.

Ventriculoperitoneal (VP) shunting remains invaluable in the management of hydrocephalus. It is a common procedure that can be complicated by shunt malfunction due to infection, blockage and disconnection. Spontaneous peritoneal catheter knot formation causing CSF flow obstruction is a rare phenomenon. We present a case of a 12years old boy with spontaneous knot formation in the peritoneal catheter causing VP shunt obstruction and hydrocephalus.

Size and Location of Ruptured Intracranial Aneurysms: A 5-Year Clinical Survey.

BACKGROUND: Prospective international cohort trials have suggested that incidental cerebral aneurysms with diameters less than 10 mm are unlikely to rupture. Consequently, small ruptured cerebral aneurysms should rarely be seen in clinical practice. To verify this theory, dimensions and locations of ruptured cerebral aneurysms were analyzed across the state of Tasmania, Australia. METHODS: We retrospectively reviewed medical records and diagnostic tests of all patients admitted with ruptured cerebral aneurysms during a 5-year interval. Aneurysm location, maximum size, dome-to-neck ratio, volume, and presence of daughter sacs were determined by preoperative digital subtraction angiography or computed tomography angiography. RESULTS: A total of 131 ruptured cerebral aneurysms were encountered and treated by microsurgical clipping (n = 59) or endovascular techniques (n = 72). The mean maximum aneurysm diameter was 6.4 ± 3.7 mm, dome-to-neck ratio 2 ± 0.8, aneurysm volume 156 ± 372 mm(3), and daughter sacs were present in 70 aneurysms (53.4%). The anterior communicating artery was the most common location (37.4%). Cumulative maximum diameters of ruptured aneurysms were ≤5 mm in 49%, ≤7 mm in 73%, and ≤10 mm in 90%. CONCLUSIONS: Despite findings from prospective international cohort trials, small ruptured intracranial aneurysms are common in clinical practice. In consequence, it seems important to identify those patients with small but vulnerable unruptured aneurysms before conservative management is considered.

Seat belt syndrome with unstable Chance fracture dislocation of the second lumbar vertebra without neurological deficits.

The seat belt syndrome is a recognised complication of seat belt use in vehicles. Unstable Chance fractures of the spine without neurological deficits have been reported infrequently. We describe a young woman with completely disrupted Chance fracture of the second lumbar vertebra in association with left hemidiaphragmatic rupture/hernia, multiple bowel perforations, splenic capsular tear, left humeral shaft and multiple rib fractures. These injuries which resulted from high-speed vehicle collision and led to death of one of the occupants were readily detected by trauma series imaging. The patient was successfully treated by a dedicated multidisciplinary team which adopted a staged surgical approach and prioritisation of care. There were no manifested neurological or other deficits after 1 year of follow-up. To the authors' knowledge, this is the first report of such a case in Australasia. We discuss the challenging surgical management, highlighting the role of radiological imaging in such cases and provide a literature review.

Successful treatment of negative pressure hydrocephalus using timely titrated external ventricular drainage: a case series.

OBJECTIVE: Negative-pressure hydrocephalus (NegPH) is a rare clinical entity characterised by enlarged ventricles and symptoms consistent with increased intracranial pressure (ICP) in the setting of negative ICP. Little has been published regarding appropriate treatment and outcomes of negative-pressure hydrocephalus patients, and no data have been published demonstrating successful therapy producing acceptable long-term outcomes. Here we present 8 cases successfully treated by titrated external ventricular drainage (TEVD), including drainage at negative (subatmospheric) pressure, and subsequent low-pressure ventriculoperitoneal shunting. METHODS: A retrospective audit of all cases of negative-pressure hydrocephalus occurring at a university teaching hospital between 2006 and 2012 was undertaken. The clinical features of these cases, results of radiological investigations, treatment, and outcome were drawn from the patients' records. RESULTS: Eight cases of NegPH were identified. All patients had at least one preceding intracranial procedure (mean number of procedures 3.0). All cases were treated using TEVD, titrated to produce between 5 and 15 mL per hour of CSF drainage, including drainage under subatmospheric pressure if this was required to maintain CSF flow. Mean delay from first negative ICP to TEVD was 1.8 days. All 8 patients demonstrated clinical improvement. TEVD resulted in improvement in Glasgow Coma Scale (mean increase 4.6, p=0.003), and increases in ICP (mean increase 8.5, p<0.001). Mean length of follow-up was 471.8 days. At follow-up, four patients had returned to pre-morbid functioning, three had a reduction in functioning attributable to their initial presentation (not NegPH), and one had died of unknown cause. Illustrative case descriptions are included. CONCLUSIONS: Negative-pressure hydrocephalus is a rare but underrecognised syndrome that can be successfully treated by timely external ventricular drainage titrated to maintain CSF flow, and subsequent low-pressure ventriculoperitoneal shunting.

A rare association of cerebral dural arteriovenous fistula with venous aneurysm and contralateral flow-related middle cerebral artery aneurysm.

The association of cerebral dural arteriovenous fistula (DAVF) and ipsilateral flow related aneurysm has infrequently been reported. We describe a male patient who presented with an acute haemorrhagic stroke and was found to have a large right fronto-parietal intra-parenchymal haemorrhage from the ruptured Borden type II DAVF in addition to a large venous aneurysm and a flow related intraosseous aneurysm of the contralateral middle meningeal artery (MMA) all clearly delineated by CT and DSA. He underwent emergency stereotactic evacuation of the intraparenchymal haemorrhage and successful surgical treatment of all the vascular lesions at the same time with residual neurological deficit. To our knowledge, this is the first such reported case. We discuss the challenging surgical treatment, emphasising the role of CT/DSA in management, and provide a literature review.

Charcot-Marie-Tooth syndrome and neurofibromatosis type 1 with multiple neurofibromas of the entire spinal nerve roots.

The coexistence of polyneuropathy which has the definite clinical and electromyographical findings consistent with Charcot-Marie-Tooth (CMT) syndrome and neurofibromatosis type 1 (NF1) has infrequently been reported. We describe a patient with both CMT and NF1, who had multiple neurofibromas involving the entire spinal neural axis. In addition, he had multiple neurofibromas distributed within the ileopsoas and gluteus muscles and subcutaneous tissues. These lesions were detected readily by MRI and the patient underwent successful surgical resection of the largest tumours compressing bilateral C2 nerve roots. To our knowledge, this is the first reported case of CMT syndrome coexisting with NF1 in which multiple neurofibromas involved the entire spinal nerve roots. We discuss the diagnostic and therapeutic challenges, emphasising the role of MRI and electrophysiology in such cases and provide a literature review.

Intramedullary spinal cord metastases: a 20-year institutional experience with a comprehensive literature review.

OBJECTIVES: To review previous reports as well as our institutional experience to address the issues regarding patient management and also to assess the predisposing factors that might influence outcome and survival. METHODS: We undertook a 20-year (1989-2009) retrospective study of a series of eight patients diagnosed with intramedullary spinal cord metastases (ISCMs) in our institute. We further reviewed 293 cases of ISCMs reported in the English literature since 1960. Characteristics regarding the site of the primary cancer, location of ISCM, the presence of other metastases, presenting neurological symptoms/signs, duration of symptoms, and the time interval from diagnosis of the primary tumor to ISCM were pooled. We analyzed the different treatment approaches, the functional outcome, and the factors influencing survival. RESULTS: Lung and breast cancers appear to be the most frequent source of ISCM with cervical, thoracic, and lumbar spine being equally affected. Motor weakness predominates as the commonest symptom at presentation, followed by pain and sensory disturbance. At diagnosis, most patients with ISCM have a known primary cancer often associated with cerebral and other systemic metastases. Overall survival of ISCM is poor (median: 4 months from the time of diagnosis). Survival in surgical patients is 6 months, compared with 5 months in those conservatively managed. Clinical improvement was observed in more than one-half of those treated surgically, whereas neurological status was maintained in most patients treated conservatively. CONCLUSION: ISCM is an unusual site for metastasis. Regardless of the treatment, its prognosis is generally poor as its presence often signifies end-stage cancer. However, with early diagnosis and appropriate treatment, selected patients may benefit from improved neurological outcome and quality of life.

Atypical meningiomas--a case series.

Meningiomas, in particular the Atypical (grade 2), vary greatly in their behaviour and prognosis. Over a 19 year period, we operated on 169 meningiomas (on 86 patients) and of those, 9 cases of atypical meningiomas were found which met the 2007 World Health Organization (WHO) classification. The 9 patients represented 5.3% of all meningiomas. The average presenting age was 51 years and average follow-up was 103 months with 5 patients passing away between 38 and 219 months after diagnosis. The time to first recurrence was 24 months with 1 patient suffering 12 recurrences and 2 cases having metastases. Although we had a small number of atypical meningiomas, we believe our paper highlights the unpredictable and difficult nature of these tumours.

An intraneural ganglion cyst causing unilateral hypoglossal nerve palsy.

Intracranial ganglion cysts are rare. We report a patient with a rare unilateral hypoglossal nerve palsy caused by an intraneural ganglion cyst. To our knowledge, there are only four reports of ganglion/synovial cysts causing unilateral hypoglossal nerve palsy. Our aim is to present the fifth report, and to compare our findings with the others.

Combined modality treatment of newly diagnosed glioblastoma multiforme in a regional neurosurgical centre.

The "local experience" of the Stupp protocol was examined in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) with particular emphasis given to the extent of surgical resection and its effect on survival. Thirty-one patients with newly diagnosed GBM who underwent combined modality treatment according to the Stupp protocol were assessed retrospectively. Variables assessed were the extent of surgery, size and site of the tumour, age and performance status. Primary end points were overall survival (OS) and progression-free survival (PFS). Median OS was 33 months for macroscopic tumour resection (9 patients; 29%), 15 months for debulking (15; 48%) and 9 months for biopsy (7; 22%). Macroscopic tumour resection resulted in significantly improved OS and PFS compared to the two less radical surgical options (p<0.001). Patients with GBM undergoing maximal resection of the tumour followed by adjuvant radiotherapy and chemotherapy have an improved survival compared to patients undergoing either subtotal resection or biopsy alone. This statistically significant survival benefit was achieved in a regional neurosurgical centre with minimal additional toxicity.

Spontaneous regression of syringomyelia--review of the current aetiological theories and implications for surgery.

A number of hypotheses have been postulated to explain the development of syringomyelia associated with Chiari I malformation. However, the mechanism of syrinx development is still poorly understood. Furthermore, the outcomes of current surgical procedures have been variable. There is evidence that the syringomyelia can spontaneously resolve, and this may warrant a more conservative approach to monitor the progression of neurological deficits. In this paper, we present a patient with spontaneous regression of syringomyelia. The current aetiological theories are discussed.

Traumatic intracranial aneurysm: a brief review.

Traumatic intracranial aneurysms are uncommon and represent fewer than 1% of all cerebral aneurysms. They may develop after blunt or penetrating head injuries and can present both diagnostic challenges and surgical difficulties. Because traumatic aneurysms are fragile and prone to rupture, early diagnosis with cerebral angiography and prompt treatment are essential. We present two patients with traumatic aneurysms and discuss their aetiology, classification, clinical presentations, diagnosis, and treatment options.

Ventriculoperitoneal shunt blockage due to spontaneous knot formation in the peritoneal catheter. Case report.

The authors report the third case of ventriculoperitoneal shunt blockage due to spontaneous knot formation in the peritoneal catheter that had been placed in a 3.5-year-old boy 8 months earlier. On surgical exploration a double knot was found 10 cm from the distal end of the peritoneal catheter. Although the underlying mechanism remains unknown, the authors used the analogy of related physical studies and true knot formation in the umbilical cord and determined the possible causes as related to the catheter, volume and configuration of the abdomen, and kinetics of the catheter movements. If further study should reveal a significantly higher incidence of this complication, the authors suggest further in vitro studies, designed to investigate the optimal characteristics and safe range of length of peritoneal catheters in different situations.

Solitary choroid plexus metastasis from carcinoma of the oesophagus.

Metastatic tumors to the brain presenting exclusively in the choroid plexus are rare and are most frequently associated with renal cell carcinoma. In this paper, the authors report an unusual case of intraventricular metastasis, and to the authors' knowledge, this is the first case of solitary metastasis from oesophageal carcinoma to the choroid plexus to be described in the literature. Metastatic disease is an important differential diagnosis which must be considered even for a patient without a documented primary malignancy who presents with a single lesion in the ventricle.

Traumatic carotid artery-cavernous sinus fistula treated with a covered stent. Report of two cases.

The authors describe the cases of two patients with unilateral traumatic caroticocavernous fistulas in whom a self-expanding covered stent was successfully used to obliterate the fistula after failed occlusion with detachable balloons and coils. They discuss this option as a primary therapeutic modality in cases in which detachable balloons or coils, with or without a bare stent, have failed to obliterate the fistula. The placement of a covered stent to occlude the lesion from the outset may represent a new therapeutic approach to the treatment of these lesions.