Circulating myomiRNAs as biomarkers in patients with Cushing's syndrome.

PURPOSE: Impairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle. METHODS: C2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation. RESULTS: HC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients. CONCLUSIONS: HC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.

Petroclival meningiomas: update of current treatment and consensus by the EANS skull base section.

BACKGROUND: The optimal management of petroclival meningiomas (PCMs) continues to be debated along with several controversies that persist. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the management of these tumors. To achieve this, the task force reviewed in detail the literature in this field and had formal discussions within the group. RESULTS: The constituted task force dealt with the existing definitions and classifications, pre-operative radiological investigations, management of small and asymptomatic PCMs, radiosurgery, optimal surgical strategies, multimodal treatment, decision-making, and patient's counselling. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the management of PCMs.

The ventral route to intracranial aneurysm: from the origin towards modern transsphenoidal surgery. An historical review and current perspective.

OBJECTIVE: A review of the main studies that have explored the use of the ventral pathway for treatment of intracranial aneurysms,including the recent reported extended transsphenoidal approaches. METHODS: A comprehensive literature review was performed using the PubMed database. We recovered 48 cases of cerebral aneurysms, approached via the transcervical-transclival, transoral-transclival, transfacial-transclival ventral pathways and the extended transsphenoidal route. The overall rates of complications and surgical success were evaluated and compared for both traditional ventral and transsphenoidal approaches. RESULTS: For traditional routes, the overall complications and surgical success rates were 74% (26/35) and 87% (13115), respectively.For extended transsphenoidal approaches were 44% (4/9) and 78% (7 /9), respectively. CONCLUSION: Our paper is a reconnaissance of what has been done via "the anterior route" and a notification of the existence of this "surgical window': Present and future of cerebral aneurysm treatment is represented by the endovascular technique. A few selected cases in specialized centers, where transsphenoidal approaches with the aid of the endoscope are routinely performed,may be treated with such techniques alone or in combination with other different procedures. Further studies in large numbers of patients will be required to validate the full benefit of this approach.

Through the orbit and beyond: Current state and future perspectives in endoscopic orbital surgery on behalf of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Introduction: Orbital surgery has always been disputed among specialists, mainly neurosurgeons, otorhinolaryngologists, maxillofacial surgeons and ophthalmologists. The orbit is a borderland between intra- and extracranial compartments; Krönlein's lateral orbitotomy and the orbitozygomatic infratemporal approach are the historical milestones of modern orbital-cranial surgery. Research question: Since its first implementation, endoscopy has significantly impacted neurosurgery, changing perspectives and approaches to the skull base. Since its first application in 2009, transorbital endoscopic surgery opened the way for new surgical scenario, previously feasible only with extensive tissue dissection. Material and methods: A PRISMA based literature search was performed to select the most relevant papers on the topic. Results: Here, we provide a narrative review on the current state and future trends in endoscopic orbital surgery. Discussion and conclusion: This manuscript is a joint effort of the EANS frontiers committee in orbital tumors and the EANS skull base section.

Clinical application of the "sellar barrier's concept" for predicting intraoperative CSF leak in endoscopic endonasal surgery for pituitary adenomas with a machine learning analysis.

Background: Recently, it was defined that the sellar barrier entity could be identified as a predictor of cerebrospinal fluid (CSF) intraoperative leakage. The aim of this study is to validate the application of the sellar barrier concept for predicting intraoperative CSF leak in endoscopic endonasal surgery for pituitary adenomas with a machine learning approach. Methods: We conducted a prospective cohort study, from June 2019 to September 2020: data from 155 patients with pituitary subdiaphragmatic adenoma operated through endoscopic approach at the Division of Neurosurgery, Università degli Studi di Napoli "Federico II," were included. Preoperative magnetic resonance images (MRI) and intraoperative findings were analyzed. After processing patient data, the experiment was conducted as a novelty detection problem, splitting outliers (i.e., patients with intraoperative fistula, n = 11/155) and inliers into separate datasets, the latter further separated into training (n = 115/144) and inlier test (n = 29/144) datasets. The machine learning analysis was performed using different novelty detection algorithms [isolation forest, local outlier factor, one-class support vector machine (oSVM)], whose performance was assessed separately and as an ensemble on the inlier and outlier test sets. Results: According to the type of sellar barrier, patients were classified into two groups, i.e., strong and weak barrier; a third category of mixed barrier was defined when a case was neither weak nor strong. Significant differences between the three datasets were found for Knosp classification score (p = 0.0015), MRI barrier: strong (p = 1.405 × 10-6), MRI barrier: weak (p = 4.487 × 10-8), intraoperative barrier: strong (p = 2.788 × 10-7), and intraoperative barrier: weak (p = 2.191 × 10-10). We recorded 11 cases of intraoperative leakage that occurred in the majority of patients presenting a weak sellar barrier (p = 4.487 × 10-8) at preoperative MRI. Accuracy, sensitivity, and specificity for outlier detection were 0.70, 0.64, and 0.72 for IF; 0.85, 0.45, and 1.00 for LOF; 0.83, 0.64, and 0.90 for oSVM; and 0.83, 0.55, and 0.93 for the ensemble, respectively. Conclusions: There is a true correlation between the type of sellar barrier at MRI and its in vivo features as observed during endoscopic endonasal surgery. The novelty detection models highlighted differences between patients who developed an intraoperative CSF leak and those who did not.

The role of OCT- angiography in predicting anatomical and functional recovery after endoscopic endonasal pituitary surgery: A 1-year longitudinal study.

PURPOSE: The purpose of this study was to investigate the changes in structural spectral-domain optical coherence tomography (SD-OCT), OCT Angiography (OCTA) parameters, and visual acuity, 1 year after endoscopic endonasal approach for the removal of an intra-suprasellar pituitary adenoma compressing optic chiasm and compare outcomes with 48 hours postoperative data. METHODS: Sixteen eyes of eight patients (4 males, 4 females, mean age 52 ± 11 years) were enrolled in this prospective study. The primary outcome was to evaluate the changes over time before and after surgery, analyzing the Best Corrected Visual Acuity (BCVA), Ganglion Cell Complex (GCC), Retinal Nerve Fiber Layer (RNFL) thicknesses, the retinal vessel density (VD) of Superficial Capillary Plexus (SCP), Deep Capillary Plexus (DCP), Radial Peripapillary Capillary (RPC) and the Foveal Avascular Zone (FAZ). The secondary outcome was to identify potential biomarkers that could predict visual acuity changes after 1-year follow-up. RESULTS: When comparing SD-OCT and OCTA measurements obtained after 1 year with those observed 48 hours after surgery, GCC and RNFL were significantly improved. After a significant reduction at 48 hours, GCC thickness showed a significant increase at 1 year after surgery (p = 0.007), while a significant restoration of RNFL thickness was found at 1 year (p = 0.005), as well as the VD of SCP, DCP, and RPC values. FAZ area did not change over time. BCVA significantly improved at each time after surgery (p = 0.037, p = 0.013). A statistically significant correlation was found between the preoperative BCVA, VD of SCP, DCP, RPC, and the postoperative BCVA at 1 year (p = 0.017, p = 0.029, p = 0.031, p = 0.023). CONCLUSION: SD-OCT and OCTA provide helpful information to identify the retinal structural and vascular improvements 1 year after surgery. OCTA parameters could serve as potential predictive markers for visual acuity recovery at long-term follow-up.

Extended endoscopic endonasal approach to the midline skull base: the evolving role of transsphenoidal surgery.

The evolution of the endoscopic endonasal transsphenoidal technique, which was initially reserved only for sellar lesions through the sphenoid sinus cavity, has lead in the last decades to a progressive possibility to access the skull base from the nose. This route allows midline access and visibility to the suprasellar, retrosellar and parasellar space while obviating brain retraction, and makes possible to treat transsphenoidally a variety of relatively small midline skull base and parasellar lesions traditionally approached transcranially. We report our current knowledge of the endoscopic anatomy of the midline skull base as seen from the endonasal perspective, in order to describe the surgical path and structures whose knowledge is useful during the operation. Besides, we describe the step-by-step surgical technique to access the different compartments, the "dangerous landmarks" to avoid in order to minimize the risks of complications and how to manage them, and our paradigm and techniques for dural and bony reconstruction. Furthermore, we report a brief description of the useful instruments and tools for the extended endoscopic approaches. Between January 2004 and April 2006 we performed 33 extended endonasal approaches for lesions arising from or involving the sellar region and the surrounding areas. The most representative pathologies of this series were the ten cranioparvngiomas, the six giant adenomas and the five meningiomas; we also used this procedure in three cases of chordomas, three of Rathke's cleft cysts and three of meningo-encephaloceles, one case of optic nerve glioma, one olfactory groove neuroendocrine tumor and one case of fibro-osseous dysplasia. Tumor removal, as assessed by post-operative MRI, revealed complete removal of the lesion in 2/6 pituitary adenomas, 7/10 craniopharyngiomas, 4/5 meningiomas, 3/3 Rathke's cleft cyst, 3/3 meningo-encephalocele. Surgical complications have been observed in 3 patients, two with a craniopharyngioma, one with a clival meningioma and one with a recurrent giant pituitary macroadenoma involving the entire left cavernous sinus, who developed a CSF leak and a second operation was necessary in order to review the cranial base reconstruction and seal the leak. One of them developed a bacterial meningitis, which resolved after a cycle of intravenous antibiotic therapy with no permanent neurological deficits. One patient with an intra-suprasellar non-functioning adenoma presented with a generalized epileptic seizure a few hours after the surgical procedure, due to the intraoperative massive CSF loss and consequent presence of intracranial air. We registered one surgical mortality. In three cases of craniopharyngioma and in one case of meningioma a new permanent diabetes insipidus was observed. One patient developed a sphenoid sinus mycosis, cured with antimycotic therapy. Epistaxis and airway difficulties were never observed. It is difficult todav to define the boundaries and the future limits of the extended approaches because the work is still in progress. Such extended endoscopic approaches, although at a first glance might be considered something that everyone can do, require an advanced and specialized training.

Remifentanil-TCI and propofol-TCI for conscious sedation during fibreoptic intubation in the acromegalic patient.

BACKGROUND AND OBJECTIVE: To evaluate the use of remifentanil-propofol administered as target-controlled infusion during awake fibreoptic intubation for anticipated difficult tracheal intubation in acromegalic patients. METHOD: In all, 20 consecutive acromegalic patients underwent elective endonasal endoscopic transsphenoidal pituitary surgery. After premedication with midazolam 0.03 mg kg(-1), initially a target-controlled infusion of remifentanil 1.0 ng mL(-1) and propofol 1.5 microg mL(-1) was started. The fibreoptic intubation was performed by the same physician experienced with the fibreoptic technique. During the fibreoptic procedure the target concentrations of remifentanil and propofol ranged between 1.0 and 5.0 ng mL(-1), and between 1.5 and 3.5 microg mL(-1), respectively. Changes in heart rate and mean arterial pressure were recorded during airway manipulation, during tracheal intubation, and at 1 and 3 min after. On the first postoperative day, patient recall and level of discomfort during fibreoptic intubation were evaluated. RESULTS: Endotracheal intubation was efficaciously and quickly secured in all patients. A significant increase in mean arterial pressure and heart rate was recorded only during tracheal intubation (P < 0.05). Oxygenation was sufficient and no bradypnea or apnoea was recorded. All patients later described their anaesthetic experience as satisfactory. During fibreoptic intubation, remifentanil (ng mL(-1)) and propofol (microg mL(-1)) mean effect-site concentrations were 3.2 +/- 0.3 and 2.0 +/- 1.0, respectively. CONCLUSION: Remifentanil and propofol target-controlled infusion provided satisfactory conscious sedation allowing for successful oral fibreoptic intubation in acromegalic patients with no recall.

Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans.

Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.

The endoscopic endonasal trans-sphenoidal approach to the sellar and suprasellar area. Anatomic study.

AIM: The microscopic trans-sphenoidal approach has been the treatment of choice of different sellar lesions over the last thirty years. However, due to several advantages brought by the endoscope, which provides a panoramic and close up view of all the anatomic landmarks either in the sphenoid sinus and in the sellar region, an increasing interest for the trans-sphenoidal approach to the sellar and suprasellar region is being noticed in the recent past years. Since the endoscopic approach drives the surgeon through a corridor whose walls were previously hidden by the nasal speculum, the precise knowledge of the endoscopic anatomy and the anatomical landmarks of the surgical approach are essential to better explore the mentioned advantages. METHODS: The endoscopic endonasal approach to the sellar region was performed in 40 adult fresh cadavers, with the aim of describing the anatomical landmarks for a safe realization of the surgical approach. RESULTS: The anatomic features and the variations of the sphenoid ostia, sphenoid sinus and septae, sella turcica, optic and carotid protuberances and their relationships have been described, as well as supra and parasellar neurovascular structures. CONCLUSION: The endoscopic endonasal trans-sphenoidal approach provides a straight approach to the sellar region, where it offers a multiangled and close-up view of all the relevant neurovascular structures.

The STE12alpha homolog is required for haploid filamentation but largely dispensable for mating and virulence in Cryptococcus neoformans.

Cryptococcus neoformans is a fungal pathogen that causes meningitis in immunocompromised hosts. The organism has a known sexual cycle, and strains of the MATalpha mating type are more virulent than isogenic MATa strains in mice, and they are more common in the environment and infected hosts. A C. neoformans homolog of the STE12 transcription factor that regulates mating, filamentation, and virulence in Saccharomyces cerevisiae and Candida albicans was identified previously, found to be encoded by a novel region of the MATalpha mating type locus, and shown to enhance filamentous growth when overexpressed. We have disrupted the C. neoformans STE12 gene in a pathogenic serotype A isolate. ste12 mutant strains exhibit a severe defect in filamentation and sporulation (haploid fruiting) in response to nitrogen starvation. In contrast, ste12 mutant strains have only modest mating defects and are fully virulent in two animal models compared to the STE12 wild-type strain. In genetic epistasis experiments, STE12 functions in a MAP kinase cascade to regulate fruiting, but not mating. Thus, the C. neoformans STE12alpha transcription factor homolog plays a specialized function in haploid fruiting, but it is dispensable or redundant for mating and virulence. The association of the MATalpha locus with virulence may involve additional genes, and other transcription factors that regulate mating and virulence remain to be identified.

Easy sellar reconstruction in endoscopic endonasal transsphenoidal surgery with polyester-silicone dural substitute and fibrin glue: technical note.

OBJECTIVE: To describe a simple method of sellar reconstruction after endoscopic endonasal transsphenoidal surgery that will allow rapid watertight closure of the sellar floor. METHODS: A bent sheet of a polyester-silicone dural substitute, fashioned for this purpose with scissors, is introduced into the sella after removal of the lesion. Because of the consistency of the sheet, it opens spontaneously and becomes stuck. Autologous fat tissue or gelatin foam is positioned thereafter, followed by another layer of the dural substitute; a film of fibrin glue completes the sealing. RESULTS: Fifteen patients underwent this method and no postoperative cerebrospinal leak or other complication was experienced. CONCLUSION: This easy method of sellar reconstruction represents an effective and fast possibility to perform the final step of the endoscopic transsphenoidal procedure, which otherwise may cause maneuverability problems in the limited space of one nostril.

Advances in trans-sphenoidal pituitary surgery.

Pituitary surgery is a continuous evolving speciality of the neurosurgeons' armamentarium, requiring precise anatomical knowledge, technical skills and integrated appreciation of the pituitary pathophysiology. Actually, it could be considered the result of a close cooperation between different specialists, i.e. the ophthalmologist, the neuroradiologist, the endocrinologist, the neurosurgeon, the pathologist, etc. In this teamwork environment each member plays his own role, offering his contribute to the final result; every effort is performed to provide patients with the best possible procedure, individually measured. The endoscopic pituitary surgery performed by means of a transsphenoidal approach perfectly fits this scenario, being though advocated as the result of an evolutionary process rather than a revolutionary one. The "pure" endoscopic transsphenoidal surgery - consisting of a whole procedure performed with the endoscope alone and without the use of any transsphenoidal retractor - offers some advantages due to the endoscope itself: a superior close-up view of the relevant anatomy, very important at the tumor/gland interface and an enlarged working angle are provided with an increased panoramic vision inside the surgical area. Results in terms of mass removal, relief of clinical symptoms, cure of the underlying disease and complication rate are similar to those reported in the major microsurgical series but patient compliance is by far better.

The extended endoscopic endonasal approach to the clivus and cranio-vertebral junction: anatomical study.

OBJECT: Lesions located in the retroclival area and at the level of the cranio-vertebral junction are typically approached through a variety of anterior, antero-lateral and postero-lateral skull-based approach, either alone or in combination. The aim of this anatomical study was to demonstrate the possibility of an endoscopic endonasal approach to the clivus and cranio-vertebral junction. MATERIALS AND METHODS: Five fresh cadaver heads injected with colored latex were used. A modified endonasal endoscopic approach was made through two nostrils in all cases. Endoscopic dissections were performed using rigid endoscopes, 4 mm in diameter, 18 cm in length, with 0 degrees lenses. RESULTS: Access to the clivus was possible using a lower trajectory when compared to that necessary for the sellar region. The sphenoid sinus is entered, and its inferior wall is completely removed, permitting the union of the sphenoidal and rhinopharyngeal parts of the clivus. The entire clivus can be removed, and the cranio-vertebral junction is opened, removing the anterior arch of atlas and the odontoid process. After the opening of the dura, the anterior surface of the pons and upper spinal cord with corresponding nerves and vasculature are visible. CONCLUSION: The endoscopic endonasal approach to the clivus and cranio-vertebral junction could be a valid alternative for surgical treatment of anterior lesions of these regions. Adequate endoscopic skill, lab training on cadavers and dedicated tools are required for clinical applications of the approach.

Clinical comparison of remifentanil-sevoflurane vs. remifentanil-propofol for endoscopic endonasal transphenoidal surgery.

BACKGROUND: Endoscopic endonasal transphenoidal surgery has been recently proposed as a minimally invasive procedure for the treatment of pituitary adenomas. The main objective of the anaesthesiologist is to induce sufficient haemodynamic control together with rapid recovery at the end of surgery. The aim of this study was to examine recovery profile, surgical operative conditions and haemodynamic differences using remifentanil infusion with either propofol target controlled infusion system or sevoflurane. METHOD: Forty-four adult patients were enrolled in a prospective, randomized, single-blind, two-group study: Group P received propofol target controlled infusion system and remifentanil; Group S received sevoflurane and remifentanil for maintenance of anaesthesia. RESULTS: No statistically significant differences between the two groups with regards to the haemodynamic changes, operative conditions as assessed by a four-step bleeding score (0-3), were obtained. Recovery times were considerably shorter after remifentanil-sevoflurane in comparison with remifentanil-propofol target controlled infusion system group (7.4 vs. 12.8 min, P < 0.01). CONCLUSION: This study demonstrates that sevoflurane-remifentanil gives a faster recovery and equivalent intraoperative status compared with propofol target controlled infusion system with remifentanil for the endoscopic endonasal transphenoidal approach.

Microsurgical repair of the facial nerve.

OBJECTIVE: To report a series of 18 patients who underwent microsurgical repair of the facial nerve using different techniques and to discuss the indications and results of facial reinnervation procedures. METHODS: Eighteen patients with post-surgical facial palsy underwent facial reinnervation using different techniques.'These included classic hypoglossal-facial anastomosis in 13 cases, one-stage hemihypoglossal-intratemporal facial nerve anastomosis and translabyrinthine removal of residual intra-canalar acoustic schwannoma in 3, hemihypoglossal-facial nerve anastomosis in one, and neurotization of facial muscles through a nerve graft in one. RESULTS: The facial muscle function improved in all patients, up to grade III in 7 cases (39 %), grade IV in 9 (50 %) and grade V in 2 (11 %). The tongue atrophy was minimal in 70.5 %, moderate in 17.5 % and severe in 12 %. The outcome was better in younger patients (less than 40 years of age) and in those with a lesser grade of preoperative facial impairment. CONCLUSIONS: The classic hypoglossal-facial anastomosis is the technique of choice in most cases. The use of the intratemporal facial nerve is indicated when removal of an intra-canalar residual schwannoma must also be performed. The neurotization of the facial muscles through a nerve graft may be used when there is no distal trunk of the facial nerve available for the anastomosis.

The role of the endoscopic transsphenoidal approach in pediatric neurosurgery.

The endoscopic endonasal transsphenoidal approach to the sellar region for the removal of pituitary adenomas and of other neoplasms in the same area has proved its reliability and effectiveness for the very wide vision it offers, coupled with minimal surgical trauma. Indications and advantages of such a technique are reported, focused on the treatment of lesions of the sellar and parasellar environment in pediatric age-group patients, and based on a consecutive series of 100 patients, 3 of them adolescents, treated during the last 3 years.

Dysembryogenetic spinal tumours in adults without dysraphism.

The authors report 15 patients with spinal intradural dysembryogenetic tumours with clinical onset in adult age in the absence of clinical and radiological signs of dysraphism. The series includes seven lipomas, four epidermoid cysts, three dermoid cysts and one teratoma. The tumour site was the thoracic region in three cases, the lumbar cord and conus in six, the cauda equina in four and the filum terminale in two. Among 14 patients operated upon, the surgical removal was complete in eight cases, subtotal in two and partial in four. Recurrence was noticed only in one subtotally resected thoracic epidermoid cyst. Magnetic resonance imaging allows a precise diagnosis of these lesions, mainly of small lipomas and dermoids of the conus and filum, where a tethered conus is responsible for clinical symptoms. Dysembryogenetic spinal rumours that become symptomatic in adult age may require surgical treatment. Reduction of the mass and release of any associated tethered neural elements are the goal of surgery for spinal lipomas, whereas epidermoid and dermoid cysts require a more radical treatment. However, even partial resections to avoid neural damage result in a good clinical outcome and very low risk of recurrence.

RAS1 regulates filamentation, mating and growth at high temperature of Cryptococcus neoformans.

Cryptococcus neoformans is a basidiomycete yeast and opportunistic human pathogen of increasing clinical importance due to the increasing population of immunocompromised patients. To further investigate signal transduction cascades regulating fungal pathogenesis, we have identified the gene encoding a RAS homologue in this organism. The RAS1 gene was disrupted by transformation and homologous recombination. The resulting ras1 mutant strain was viable, but failed to grow at 37 degrees C, and exhibited significant defects in mating and agar adherence. The ras1 mutant strain was also avirulent in an animal model of cryptococcal meningitis. Reintroduction of the wild-type RAS1 gene complemented these ras1 mutant phenotypes and restored virulence in animals. A dominantly active RAS1 mutant allele, RAS1Q67L, induced a differentiation phenotype known as haploid fruiting, which involves filamentation, agar invasion and sporulation in response to nitrogen deprivation. The ras1 mutant mating defect was suppressed by overexpression of MAP kinase signalling elements and partially suppressed by exogenous cAMP. Additionally, cAMP also suppressed the agar adherence defect of the ras1 mutant. However, the ability of the ras1 mutant strain to grow at elevated temperature was not restored by cAMP or MAP kinase overexpression. Our findings support a model in which RAS1 signals in C. neoformans through cAMP-dependent, MAP kinase, and RAS-specific signalling cascades to regulate mating and filamentation, as well as growth at high temperature which is necessary for maintenance of infection.