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Despite being a common procedure, cranioplasty (CP) is associated with a variety of serious, at times lethal, complications. This study explored the relationship between the initial injury leading to decompressive craniectomy (DC) and the rates and types of complications after subsequent CP. It specifically compared between traumatic brain injury (TBI) patients and patients undergoing CP after DC for other indications.A comprehensive search of PubMed, Scopus, and the Cochrane Library databases using PRISMA guidelines was performed to include case-control studies, cohorts, and clinical trials reporting complication data for CP after DC. Information about the patients’ characteristics and the rates of overall and specific complications in TBI and non-TBI patients was extracted, summarized, and analyzed.A total of 59 studies, including the authors’ institutional experience, encompassing 9264 patients (4671 TBI vs. 4593 non-TBI) met the inclusion criteria; this total also included 149 cases from our institutional series. The results of the analysis of the published series are shown both with and without our series 23 studies reported overall complications, 40 reported infections, 10 reported new-onset seizures, 13 reported bone flap resorption (BFR), 5 reported post-CP hydrocephalus, 10 reported intracranial hemorrhage (ICH), and 8 reported extra-axial fluid collections (EFC). TBI was associated with increased odds of BFR (odds ratio [OR] 1.76, p < 0.01) and infection (OR 1.38, p = 0.02). No difference was detected in the odds of overall complications, seizures, hydrocephalus, ICH, or EFC.Awareness of increased risks of BFR and infection after CP in TBI patients promotes the implementation of new strategies to prevent these complications especially in this category of patients.

In immunocompetent animals, numerous factors including the immune system of the host regulate the survival of neuro-glial precursors transplanted into the cerebellum. We transplanted human neuro-glial precursors derived in vitro from partial differentiation of IPS cells into the developing cerebellum of mice and rats before maturation of the host immune system. These approaches should facilitate the development of immune-tolerance for the transplanted cells. However, we found that human cells survived the engraftment and integrated into the host cerebellum and brain stem up to about 1 month postnatally when they were rejected in both species. On the contrary, when we transplanted the same cells in NOD-SCID mice, they survived indefinitely. Our findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts the induction of immune-tolerance to human antigens expressed before completion of the maturation of the immune system. As predicted by our hypothesis, when we engrafted the human neuro-glial precursor cells either in a more mature state or mixed with extracts from adult cerebellum, we prolonged the survival of the graft.

Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD).

We xeno-transplanted human neural precursor cells derived from induced pluripotent stem cells into the cerebellum and brainstem of mice and rats during prenatal development or the first postnatal week. The transplants survived and started to differentiate up to 1 month after birth when they were rejected by both species. Extended survival and differentiation of the same cells were obtained only when they were transplanted in NOD-SCID mice. Transplants of human neural precursor cells mixed with the same cells after partial in vitro differentiation or with a cellular extract obtained from adult rat cerebellum increased survival of the xeno-graft beyond one month. These findings are consistent with the hypothesis that the slower pace of differentiation of human neural precursors compared to that of rodents restricts induction of immune-tolerance to human antigens expressed before completion of maturation of the immune system. With further maturation the transplanted neural precursors expressed more mature antigens before the graft were rejected. Supplementation of the immature cells suspensions with more mature antigens may help to induce immune-tolerance for those antigens expressed only later by the engrafted cells.

Background Ventriculoatrial shunts were one of the most common treatments of hydrocephalus in pediatric and adult patients up to about 40 years ago. Thereafter, due to the widespread recognition of the severe cardiac and renal complications associated with ventriculoatrial shunts, they are almost exclusively implanted when other techniques fail. However, late infection or atrial thrombi of previously implanted shunts require removal of the atrial catheter several decades after implantation. Techniques derived from management of central venous access catheters can avoid cardiothoracic surgery in such instances. Methods We retrospectively investigated all the patients requiring removal of a VA shunt for complications treated in the last 5 years in our institution. Results We identified two patients that were implanted 28 and 40 years earlier. Both developed endocarditis with a large atrial thrombus and were successfully treated endovascularly. The successful percutaneous removal was achieved by applying, for the first time in this setting, the endoluminal dilation technique as proposed by Hong. After ventriculoatrial shunt removal and its substitution with an external drainage, both patients where successfully weaned from the need for a shunt and their infection resolved. Conclusion Patients carrying a ventriculoatrial shunt are now rarely seen and awareness of long-term ventriculoatrial shunt complications is decreasing. However, these complications must be recognized and treated by shunt removal. Endovascular techniques are appropriate even in the presence of overt endocarditis, atrial thrombi, and tight adherence to the endocardial wall. Moreover, weaning from shunt dependence is possible even decades after shunting.

Objective The incidence of chronic Subdural hematoma (cSDH) is increasing and its rate of recurrence varies from 5 to 33%. A postoperative brain midline-shift (MLS) on computed tomography (CT) equal or larger than 5 mm is a risk factor for recurrence. Transcranial color-coded duplex sonography (TCCDS) is a noninvasive bedside reproducible technique useful to detect MLS. The aim of our study was to compare in patients affected by cSDH, the values of MLS obtained pre- and post-operatively by TCCDS and brain CT. Patients and methods 32 patients affected by cSDH entered the study between July 2016 and January 2017. MLS values obtained by TCCDS and brain CT were compared using Bland-Altman plot and linear regression analysis. Using the same techniques we also explored if the agreement between the two imaging modes was comparable in pre- and post-operative data pairs. Results 64 data pairs of MLS values obtained by TCCDS and CT were analysed. Bland-Altman diagrams did not show any systematic bias of the data and linear regression indicated a significant correlation between the two measures both before and after hematoma evacuation. Conclusion In patients affected by cSDH, MLS values obtained before and after surgery by TCCDS are comparable to those obtained by CT; TCCDS might be considered an alternative to CT scan in the management of patients after cSDH evacuation. We suggest that close clinical bedside examination and TCCDS might be appropriate for the post-operative management of cSDH, reserving CT scan only to patients with overt clinical deterioration and/or increasing MLS.

Introduction: Spinal epidural abscess (SEA) incidence is rising. However, most series do not differentiate between SEAs associated with pyogenic infectious spondylodiscitis (PS) and SEAs limited to the epidural space. Methods: We retrospectively reviewed the records and radiological images of all patients admitted to our institutions with a diagnosis of SEA not associated with PS between January 2013 and December 2018. Results: We found three males and four females; five of the seven were intravenous drug users. All patients presented with pain: in six, it was associated with acute motor and sensory deficits, while one had only pain and paresthesias. Staphylococcus aureus was cultured from abscesses and/or from multiple blood cultures in four patients. Abscesses were localized to the cervical spine in one patient, thoracic in three, lumbar in one, and in two, the SEAs involved multiple segments. All patients but one underwent urgent open surgery. This patient had a multisegmental abscess and was successfully treated by percutaneous aspiration when pain became intractable. After abscess evacuation, the neurological deficits improved in all patients except one. The patients that were treated without spine instrumentation did not develop delayed kyphosis or instability at follow-up. Conclusion: Patients with SEAs not associated with PS are likely to present with pain and motor deficits, appear to benefit from urgent abscess evacuation, and seem to be less dependent on spine instrumentation to avoid delayed spinal deformities compared to SEA associated with PS. Finally, the lack of initial involvement of bone and intervertebral disks may suggest that at least some of the SEAs without PS originate from infection of epidural lymphatic vessels that are not present inside those structures.

Restoration of damaged central nervous system structures, functional recovery, and prevention of neuronal loss during neurodegenerative diseases are major objectives in cerebellar research. The highly organized anatomical structure of the cerebellum with numerous inputs/outputs, the complexity of cerebellar functions, and the large spectrum of cerebellar ataxias render therapies of cerebellar disorders highly challenging. There are currently several therapeutic approaches including motor rehabilitation, neuroprotective drugs, non-invasive cerebellar stimulation, molecularly based therapy targeting pathogenesis of the disease, and neurotransplantation. We discuss the goals and possible beneficial mechanisms of transplantation therapy for cerebellar damage and its limitations and factors determining outcome.

OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale–Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 (ClinicalTrials.gov)

Background Spinal epidural cavernous hemangiomas are rare vascular malformations. Exceptionally, they present with dumbbell-shaped morphology. When they happen, it's mandatory to include their pathology in the differential diagnosis because of their similarity to schwannomas. Case Description We report the case of a 72-year-old woman with a dumbbell-shaped thoracic epidural cavernous hemangioma. A literature review of diagnostic features and current treatment options are also discussed. Conclusions Surgery is safe and effective in both improving patient condition and preventing acute hemorrhage that can worsen the outcome, causing neurologic and potentially irreversible deficits. The favorable result we obtained in our patient suggests that surgery should be evaluated as the first option, even in patients with large epidural cavernous hemangiomas.

An infrequent and difficult to treat complication of the neurosurgical removal of a lesion in the frontal or parietal lobes is cortical myoclonus (CM).1,2 CM has also been linked to focal lesions in the same locations independently from their surgical removal.3-5 In the present case and in the majority of the reported cases, the paramedian premotor cortex was involved. However, all except one of the lesions that were previously reported were not adjacent to the primary motor cortex as in our patient (figure, A). Treatment of myoclonus can be difficult and polytherapy is often required for an acceptable result.6 We present a case of CM that started 5 days after surgery, was not responsive to benzodiazepine and levetiracetam, and resolved only after perampanel administration.

The lack of direct neurophysiological recordings from the thalamus and the cortex hampers our understanding of vegetative state/unresponsive wakefulness syndrome and minimally conscious state in humans. We obtained microelectrode recordings from the thalami and the homolateral parietal cortex of two vegetative state/unresponsive wakefulness syndrome and one minimally conscious state patients during surgery for implantation of electrodes in both thalami for chronic deep brain stimulation. We found that activity of the thalamo-cortical networks differed among the two conditions. There were half the number of active neurons in the thalami of patients in vegetative state/unresponsive wakefulness syndrome than in minimally conscious state. Coupling of thalamic neuron discharge with EEG phases also differed in the two conditions and thalamo-cortical cross-frequency coupling was limited to the minimally conscious state patient. When consciousness is physiologically or pharmacologically reversibly suspended there is a significant increase in bursting activity of the thalamic neurons. By contrast, in the thalami of our patients in both conditions fewer than 17% of the recorded neurons showed bursting activity. This indicates that these conditions differ from physiological suspension of consciousness and that increased thalamic inhibition is not prominent. Our findings, albeit obtained in a limited number of patients, unveil the neurophysiology of these conditions at single unit resolution and might be relevant for inspiring novel therapeutic options.

Pupil size is governed by the synergic action of the Autonomic Nervous System. Pupil Diameter (PD) is primarily influenced by the light level and it is responsive to variations of global luminance level. However, recent studies have shown that there is also a high-level interpretation which could modulate this physiological response. In this paper, we develop an ad-hoc protocol based on iso-luminant stimuli and validate its effectiveness for the analysis of high-level modulation of pupil response. A visual illusion was reproduced from literature and adapted in two different colors. Prior to the response analysis, a reconstruction of the missing data due to blinks and other artifacts were reconstructed by using a recently developed signal reconstruction algorithm (Iterative - Single Spectrum Analysis: I-SSA); then both time and frequency domain parameters were extracted from the PD signal. Results indicate that there are peculiarly different responses to iso-luminant stimuli with different image structures and dominating colors, thus indicating a possible high-level processing mechanism. Our results pave the way for future evaluation of comatose or generic unconscious state based on non-contact pupil dynamics assessment.

How language is encoded by neural activity in the higher-level language areas of humans is still largely unknown. We investigated whether the electrophysiological activity of Broca's area correlates with the sound of the utterances produced. During speech perception, the electric cortical activity of the auditory areas correlates with the sound envelope of the utterances. In our experiment, we compared the electrocorticogram recorded during awake neurosurgical operations in Broca's area and in the dominant temporal lobe with the sound envelope of single words versus sentences read aloud or mentally by the patients. Our results indicate that the electrocorticogram correlates with the sound envelope of the utterances, starting before any sound is produced and even in the absence of speech, when the patient is reading mentally. No correlations were found when the electrocorticogram was recorded in the superior parietal gyrus, an area not directly involved in language generation, or in Broca's area when the participants were executing a repetitive motor task, which did not include any linguistic content, with their dominant hand. The distribution of suprathreshold correlations across frequencies of cortical activities varied whether the sound envelope derived from words or sentences. Our results suggest the activity of language areas is organized by sound when language is generated before any utterance is produced or heard.

A wide range of studies on language assessment during awake brain surgery is nowadays available. Yet, a consensus on a standardized protocol for intraoperative language mapping is still lacking. More specifically, very limited information is offered about intraoperative assessment of a crucial component of language such as syntax. This review aims at critically analyzing the intraoperative studies investigating the cerebral basis of syntactic processing. A comprehensive query was performed on the literature, returning a total of 18 studies. These papers were analyzed according to two complementary criteria, based on the distinction between morphosyntax and syntax. The first criterion focused on the tasks and stimuli employed intraoperatively. Studies were divided into three different groups: group 1 included those studies that overtly aimed at investigating morphosyntactic processes; group 2 included studies that did not explicitly focus on syntax, yet employed stimuli requiring morphosyntactic processing; and group 3 included studies reporting some generic form of syntactic deficit, although not further investigated. The second criterion focused on the syntactic structures of the sentences assessed intraoperatively, analyzing the canonicity of sentence structure (i.e., canonical versus non-canonical word order). The global picture emerging from our analysis indicates that what was investigated in the intraoperative literature is morphosyntactic processing, rather than pure syntax. The study of the neurobiology of syntax during awake surgery seems thus to be still at an early stage, in need of systematic, linguistically grounded investigations.

Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glucose antiporter type 2 (SGLT2/SLC5A2) superfamily, phlorizin (PHZ), in decreasing glucose consumption and cell proliferation of human and murine glioblastoma cells. We found in vitro that RTV, active on at least three different GLUT/SLC2A transporters, was more effective than IDV, a specific inhibitor of GLUT4/SLC2A4, both in decreasing glucose consumption and lactate production and in inhibiting growth of U87MG and Hu197 human glioblastoma cell lines and primary cultures of human glioblastoma. PHZ was inactive on the same cells. Similar results were obtained when cells were grown in adherence or as 3D multicellular tumor spheroids. RTV treatment but not IDV treatment induced AMP-activated protein kinase (AMPKα) phosphorylation that paralleled the decrease in glycolytic activity and cell growth. IDV, but not RTV, induced an increase in GLUT1/SLC2A1 whose activity could compensate for the inhibition of GLUT4/SLC2A4 by IDV. RTV and IDV pass poorly the blood brain barrier and are unlikely to reach sufficient liquoral concentrations in vivo to inhibit glioblastoma growth as single agents. Isobologram analysis of the association of RTV or IDV and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide (TMZ) indicated synergy only with RTV on inhibition of glioblastoma cells. Finally, we tested in vivo the combination of RTV and BCNU on established GL261 tumors. This drug combination increased the overall survival and allowed a five-fold reduction in the dose of BCNU.

Shc3 protein levels are high in human glioblastoma but they decrease in vitro. We found that SHC3 mRNA and protein increased when glioblastoma cells grew as multicellular tumor spheroid (MTS). Shc3 expression was also induced in adherent cultures by increasing cell density. Among the Shc family members, only Shc2 and Shc3 increased with cell density. Shc3 and focal adhesion kinase (Fak) interact as shown by co-immunoprecipitation. Inhibition of Fak activation reduced Shc3 increase and MTS formation and changed Shc3 phosphorylation pattern. Our results suggest that in gliomas cell density modulates Shc3 protein levels and its activity, at least in part, through Fak activation.

OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale-Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 ( ClinicalTrials.gov ).

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) is characterized by abrupt onset of symptoms generally associated with focal brain lesions and inflammatory CSF findings. A previously asymptomatic 31-year-old HIV+ woman presented with acute cognitive difficulties, right hemiparesis and dysphasia. Brain MRI showed a large contrast-enhancing lesion in the left frontal lobe; brain biopsy revealed an inflammatory process. No etiological agent was found in blood, CSF or brain tissue. The patient was given systemic steroids and gammaglobulins and put on HAART. Clinical conditions progressively and completely recovered. Further brain MRI showed the shrinkage of the lesion with no contrast enhancement. Our case could be classified as AIL in HIV resembling ADEM pattern and highlights the importance of taking into consideration. ADEM in the diagnostic process of HIV-related leukoencephalopathy even if the typical features are lacking, as immunodeficiency could modify both presentation and disease course.

By qPCR we found that EDG3 and SHC3 were amplified in 60% of ependymomas but none in choroid plexus papillomas. In ependymomas EDG3 and SHC3 amplification increased Shc3 protein levels while EDG3 was less affected. Both proteins were co-immunoprecipitated from ependymoma and Shc3 was tyrosine phosphorylated thus presumably active. We showed by digestion with N-glycosidase-F that EDG3 was glycosylated indicating that EDG3 protein was not retained in the endoplasmic reticulum. The co-immunoprecipitation of Shc3 and EDG3 proteins from ependymomas with amplification of SHC3 and EDG3 genes suggests that the two proteins co-operate and are important for ependymomas in vivo.

In most CNS regions, the variety of inhibitory interneurons originates from separate pools of progenitors residing in discrete germinal domains, where they become committed to specific phenotypes and positions during their last mitosis. We show here that GABAergic interneurons of the rodent cerebellum are generated through a different mechanism. Progenitors for these interneurons delaminate from the ventricular neuroepithelium of the embryonic cerebellar primordium and continue to proliferate in the prospective white matter during late embryonic and postnatal development. Young postmitotic interneurons do not migrate immediately to their final destination, but remain in the prospective white matter for several days. The different interneuron categories are produced according to a continuous inside-out positional sequence, and cell identity and laminar placement in the cerebellar cortex are temporally related to birth date. However, terminal commitment does not occur while precursors are still proliferating, and postmitotic cells heterochronically transplanted to developing cerebella consistently adopt host-specific phenotypes and positions. However, solid grafts of prospective white matter implanted into the adult cerebellum, when interneuron genesis has ceased, produce interneuron types characteristic of the donor age. Therefore, specification of cerebellar GABAergic interneurons occurs through a hitherto unknown process, in which postmitotic neurons maintain broad developmental potentialities and their phenotypic choices are dictated by instructive cues provided by the microenvironment of the prospective white matter. Whereas in most CNS regions the repertoire of inhibitory interneurons is produced by recruiting precursors from different origins, in the cerebellum it is achieved by creating phenotypic diversity from a single source.

Temozolomide (TMZ) and carmustine (BCNU), cancer-drugs usually used in the treatment of gliomas, are DNA-methylating agents producing O6-methylguanine. It has been shown that 06-methylguanine triggers DNA mismatch repair and in turn induce apoptosis and senescence, respectively, over a 4 and 6 days period [Y. Hirose, M.S. Berger, R.O. Pieper, p53 effects both the duration of G2/M arrest and the fate of temozolomide-treated human glioblastoma cells, Cancer Res. 61 (2001) 1957–1963; W. Roos, M. Baumgartner, B. Kaina, Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1, Oncogene 23 (2004) 359–367]. Here we show that TMZ and BCNU have an earlier effect on nuclear organization and chromatin structure. In particular, we report that TMZ and BCNU induce clustering of pericentromeric heterochromatin regions and increase the amount of heterochromatic proteins MeCP2 and HP1α bound to chromatin. These drugs also decrease global levels of histone H3 acetylation and increase levels of histone H3 trimethylated on lysine 9 (H3-triMeK9). These events precede the senescence status. We conclude that TMZ and BCNU efficacy in glioma treatment may implicate a first event characterized by changes in heterochromatin organization and its silencing which is then followed by apoptosis and senescence.

In this report we describe a patient with a tight filum associated with a small concentric lipoma that was treated by cutting the filum terminale through a totally endoscopic approach. Our approach required the creation of a midline surgical corridor provided by the placement of a telescopic self-retaining retractor over the ligamentum flavum at L5-S1, under endoscopic control. The ligamentum was partially removed, the dura and the arachnoid opened and the filum terminale and the roots of the cauda exposed. After neurophysiological confirmation of the absence of neural structures the filum was coagulated and cut, the dura was closed by a continuous suture and sealed with fibrin glue. The entire surgery was performed under the illumination and magnification provided by a rigid endoscope working in an aerial environment. This case shows that the cauda can be explored and the filum terminale cut with a minimally invasive endoscopic approach that does not significantly compromise the structural integrity of the spine, requires only a short dural incision, therefore reducing the risk of postoperative cerebrospinal fluid leakage, and allows the use of multiple surgical instruments in an aerial environment.

To introduce a novel approach for the monitoring of glioma evolution by the extraction of mathematical parameters from follow-up MRI. The method consists of the registration of follow-up MR images and the analysis of the deformation field. The registration was performed through an affine transformation followed by a non-rigid registration using free-form deformations (FFDs). A subsequent analysis of the transformation non-linear component is then performed by using the jacobian operator in order to extract information related to tumor evolution. In order to test the algorithm’s performance two different validations were performed: (a) a numerical validation utilizing both physical and digital phantoms, (b) a clinical validation using neurosurgeon clinical judgements. Quantitative validation showed that the jacobian describes the volumetric variations of the physical phantom with an error of 5%. Furthermore, simulations with a digital phantom provided an estimation of the error introduced by registration (6.4%). Clinical validation provided good clinical scores: the score evaluating the correspondence between extracted variables and patient evolution was 4.37 ± 0.89 for the deformation field and 4.43 ± 0.82 for the jacobian image (top score: 5). The novel approach leads to an objective and quantitative description of tumor evolution. Therefore, it could be valuable for planning interventions and/or treatments.

CNS repair by cell transplantation requires new neurons to integrate into complex recipient networks. We assessed how the migratory route of transplanted granule neurons and the developmental stage of the host rat cerebellum influence engraftment. In both embryonic and postnatal hosts, granule cells can enter the cerebellar cortex and achieve correct placement along their natural migratory pathway. Donor neurons can also reach the internal granular layer from the white matter and integrate following an unusual developmental pattern. Although the frequency of correct positioning declines in parallel with cortical development, in mature recipients correct homing is more frequent through the unusual path. Following depletion of granule cell precursors in the host, more granule neurons engraft, but their ability for achieving correct placement is unchanged. Therefore, while the cerebellar environment remains receptive for granule cells even after the end of development, their full integration is partially hindered by the mature cortical architecture.

Biopsies of clival lesions are usually performed, under general anaesthesia, through an anterior endoscopic approach or, alternatively, through a trans-nasal or trans-oral stereotactic approach. A 57-year-old man with a symptomatic osteolytical lesion of the clivus, who refused general anaesthesia, underwent a sterotactically guided biopsy of the lesion by an antero-lateral approach through the temporal and sphenoid bones. Biopsy was successfully performed and the resulting diagnosis was myeloma. The patient was comfortable during and after surgery and there were no complications. The present stereotactic antero-lateral approach to the biopsy of the upper clivus can be considered an useful adjunct to the current trans-oral and transnasal approaches that often require general anaesthesia.

Neoplastic meningitis is a central nervous system complication that occurs in 3–5% of patients with cancer. Although most commonly seen in patients with disseminated disease, in a small percentage of patients, it may be the initial manifestation of cancer or even primitive in origin. In the absence of cancer history, the diagnosis of neoplastic meningitis may be challenging even for expert neurologists. Prognosis is poor, with a median overall survival of weeks from diagnosis. In the retrospective study herein, we described three cases of meningeal melanomatosis in patients without previous cancer history. The patients were diagnosed with significant delay (17 to 47 weeks from symptom onset) mainly due to the deferral in performing the appropriate testing. Even when the diagnosis was suspected, investigations by MRI, cerebrospinal fluid, or both proved at times unhelpful for confirmation. Prognosis was dismal, with a median survival of 4 weeks after diagnosis. Our observations are a cue to analyze the main pitfalls in the diagnosis of neoplastic meningitis in patients without cancer history and emphasize key elements that may facilitate early diagnosis.

Il 6 febbraio 2012 l’Organismo italiano di contabilità (Oic) ha posto in consultazione pubblica sul proprio sito, fino al 10 aprile, le due bozze di principi contabili nazionali «Le quote di emissione di gas ad effetto serra» (greenhouse gases – Ghg) e «I certificati verdi». Il primo dei due standard ha lo scopo di fornire indicazioni in merito alla disciplina, alla valutazione e alla contabilizzazione in bilancio dei diritti di emissione di gas ad effetto serra (cd. «certificati grigi»), strumenti mediante i quali si incentiva la riduzione delle emissioni di CO2 e degli altri Ghg. Il secondo standard ha ad oggetto la contabilizzazione dei certificati verdi, certificati che il Gestore dei servizi energetici (Gse) emette a consuntivo o a preventivo in ragione, rispettivamente, della produzione effettiva o attesa di energia elettrica da fonti rinnovabili, secondo i meccanismi di incentivazione introdotti a partire dal 1999 (D.Lgs. 16 marzo 1999, n. 79, cd. «Decreto Bersani», e D.M. 11 novembre 1999) in materia di liberalizzazione del settore elettrico. Il presente contributo analizza in chiave critica i due standard contabili succitati

Il presente contributo, dopo aver delineato il quadro di riferimento a livello internazionale sui dati riguardanti le esternalità, i relativi costi ambientali e gli investimenti socialmente responsabili, si focalizza sul tema dell’integrated reporting (Ir) e sulle principali criticità riscontrate nei documenti tecnici che ne hanno finora indicato gli obiettivi e i tratti salienti.

Objective Intravenous (IV) injection is currently the normal method for transplanting hematopoietic cells. However, the problem of seeding efficiency and homing is relevant especially when a limited number of stem cells is available. Intra–bone marrow (IBM) injection of bone marrow cells (BMCs) may overcome this problem. Materials and methods Irradiated (750 cGy) C57BL/6J mice were transplanted with 1 × 10 5 BMCs harvested from transgenic mice expressing an enhanced version of the green fluorescent protein (EGFP + ) via IBM or with 1 × 10 6 EGFP + BMCs via IV. Irradiated (320 cGy) NOD/SCID mice were transplanted with 1 × 10 6 human cord blood (CB) cells via IBM or with 1 × 10 7 human CB cells via IV. Results In C57BL/6J mice after 90 days, the fraction of EGFP + cells harvested was 37% and 53% in IV-treated and IBM-treated (contralateral tibia and femur in the IBM) mice, respectively: the expansion folds were 114 and 1760, respectively. In NOD/SCID mice, the percentages of CD45 + cells and CD45 + /CD34 + cells were, at 30 days, 3.3% and 0.3% in IV-treated mice, and 4.4% and 1.1% in IBM-treated mice. At 60 days, the percentages of CD45 + cells and CD45 + /CD34 + cells were 2.1% and 0.3% in IV-treated mice and 1.4% and 0.4% in IBM-treated mice. At day 90 the percentages of CD45 + cells and CD45 + /CD34 + cells were 3% and 0.3% in IV-treated mice and 2.3% and 0.4% in IBM-treated mice. Conclusion Our data demonstrate that IBM transplantation is associated with a seeding efficiency 15 times greater than IV transplantation. IBM transplantation may improve the results of transplant and may be useful in several settings: 1) when a limited number of hematopoietic progenitors are available; and 2) in experiments aiming to place in the bone marrow stem cells of other lineages (CNS, muscle, etc.).

Retroviral-mediated gene transfer of the IL-4 gene into experimental gliomas can cause tumor rejection, supporting the clinical use of this form of gene therapy for glioblastomas (GBM). In a clinical setting, the administration of dexamethasone (dex) is a standard procedure for GBM patients. This led us to examine the effects of dex on IL-4 gene therapy. We injected intracranially Fischer 344 rats with phosphate-buffered saline, 9L gliosarcoma cells mixed with E86.L4SN(200) cells (retroviral producer cells, RPC, transducing IL-4 cDNA) and 9L cells mixed with PA317.STK.SBA cells (control RPC expressing the HSV-tk gene). The rats from each group were treated with 0, 50, 100 or 250 microg dex/kg/day released by osmotic pumps implanted subcutaneously. While 80-100% of rats receiving 9L cells mixed with IL-4 RPC and not treated by dex survived for at least 2 months following tumor injection, only 50% and 17% of rats receiving 50 or 100 microg/kg/day of dex, respectively, reached this time point. These results indicate that dex significantly diminished the anti-tumor effect of IL-4. Thus, in a clinical setting, IL-4 gene transfer should be performed when low levels of dex are administered or in the absence of dex.

The different cerebellar phenotypes are generated according to a precise time schedule during embryonic and postnatal development. To assess whether the differentiative potential of cerebellar progenitors is progressively restricted in space and time we examined the fate of embryonic day 12 (E12) or postnatal day 4 (P4) cerebellar cells after heterotopic-heterochronic transplantation into the embryonic rat brain in utero or into organotypic CNS explants in vitro. Donor cells, isolated from transgenic mice overexpressing the enhanced-green fluorescent protein under the control of the beta-actin-promoter, engrafted throughout the host brainstem and diencephalon, whereas they rarely incorporated into specific telencephalic structures. In any recipient site, the vast majority of transplanted cells could be recognized as cerebellar phenotypes, and we did not obtain clear evidence that ectopically located cells adopted host-specific identities. Nevertheless, the two donor populations displayed different developmental potentialities. P4 progenitors exclusively generated granule cells and molecular layer interneurons, indicating that they are committed to late-generated cerebellar identities and not responsive to heterotopic-heterochronic environmental cues. In contrast, E12 precursors had the potential to produce all major cerebellar neurons, but the repertoire of adult phenotypes generated by these cells was different in distinct host regions, suggesting that they require instructive environmental information to acquire mature identities. Thus, cerebellar precursors are able to integrate into different foreign brain regions, where they develop mature phenotypes that survive long after transplantation, but they are committed to cerebellar fates at E12. Embryonic progenitors are initially capable, although likely not competent, to generate all cerebellar identities, but their potential is gradually restricted toward late-generated phenotypes.

Abstract —The role of signal transducers and activators of transcription (STAT) proteins in modulating proliferation and differentiation of various cell types in the hematopoietic system and the central nervous system has been well established. In contrast, the pathophysiological role of these proteins in vascular proliferative diseases has remained unproven, despite in vitro observations emphasizing the involvement of the STAT system in mediating vascular smooth muscle cell (VSMC) proliferation. On the basis of our previous observations demonstrating the occurrence of a specific modulation of Stat6 protein during the proliferative, migratory, and differentiation phases of the developing brain, we investigated whether Stat6 protein is present and modulated in arterial tissue challenged by perivascular injury. The time course of expression and localization of Stat6 after arterial injury was analyzed by immunohistochemistry, Western blot analysis, and confocal microscopy. Six hours after injury, the expression of Stat6 was markedly increased. This overexpression preceded the onset of VSMC proliferation and was downregulated starting from 7 days after injury, coincident with the decline of VSMC proliferation. Moreover, early after injury, Stat6 was predominantly localized at the nuclear level, denoting its functional activation. Conversely, Stat6 staining at later time points was largely cytosolic, suggesting silencing effects of this signaling pathway. These data indicate that Stat6 signaling may contribute to the modifications of gene expression underlying VSMC activation in the context of acute vascular proliferative diseases.