MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cell (MSC) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes in MSC epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1.1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU-Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation, and cell metabolism networks in MDS-MSCs.

Line-field confocal optical coherence tomography of psoriasis, eczema and lichen planus: a case series with histopathological correlation.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is a novel, non-invasive technique that provides in vivo, high-resolution images in both vertical and horizontal sections. OBJECTIVES: The aim of the study was to evaluate LC-OCT imaging in some inflammatory disorders and to correlate the resulting features with histopathology. METHODS: The retrospective study included patients with histopathological confirmed diagnosis of plaque psoriasis, atopic eczema and lichen planus, who were imaged with LC-OCT before the biopsy. LC-OCT was performed with the commercially available LC-OCT device. RESULTS: A total of 15 adult patients with histopathologically proven plaque psoriasis (N: 5), atopic eczema (N: 5) and lichen planus (N: 5) were included. In all cases, LC-OCT allowed the in vivo recognition of the main microscopic features of the examined inflammatory skin disease, with a strong correlation with histopathology. CONCLUSIONS: Although future studies on larger series of patients are necessary, LC-OCT, based on these preliminary findings, may represent a promising tool in inflammatory skin disorders with potential applications including enhanced diagnosis, biopsy guidance, follow-up and treatment monitoring.

Dermatofibrosarcoma protuberans: a tumor in the wide spectrum of the bland-looking spindle cell lesions of the breast.

Dermatofibrosarcoma protuberans (DFSP) is a soft tissue tumor, usually occurring as a cutaneous lesion localized to the trunk or extremities; although it has a high rate of local recurrence, its metastatic potential is very low and complete surgical excision is frequently curative. Most of the cases reported as "DFSP of the breast" are tumors arising in the subcutaneous tissue infiltrating the underlying breast parenchyma. To the best of our knowledge, only 5 cases of DFSP of the breast have been reported to date. We herein present a rare case of DFSP of the breast parenchyma in a 41-year-old female with emphasis on the diagnostic clues and the differential diagnosis with other benign and malignant spindle cell lesions of the breast.

A survey around the Italian pediatric units on current clinical practice for Sleep Disordered Breathing (SDB).

BACKGROUND: During recent years, interest on Sleep Disordered Breathing (SDB) in pediatric age has increased, due to the impact on quality of life, psycho-physical attitude and other serious morbidities if undiagnosed and untreated. METHODS: Italian Pediatric Respiratory Diseases Society (SIMRI) SDB-Working Group carried out an exploratory survey in Italy, from January to December 2016, to assess the diagnostic and therapeutic pathways, perception and relevance of SDB in Italian Hospitals. RESULTS: A questionnaire was sent to 180 Pediatric Units (PUs) distributed throughout the Italy; 102 Pediatric Units (PUs; 56.6%) answered and among them 57% dealt with SDB, and 94% recognized SDB as a major problem. Instrumental tests performed by the PUs were saturimetry (66%), nocturnal polygraphy with complete cardio-respiratory monitoring (46%) and full polysomnography (23%). In addition, hospital pediatricians reported that 54% of parents were unaware of the SDB and 84% did not know their complications. In the Northern Italy, the diagnosis was frequently performed with instrumental tools and the treatment was often surgical. In the Southern Italy the diagnosis was clinical, and the treatment was usually with drugs. CONCLUSIONS: The results of our study showed a heterogeneity in the diagnosis and treatment of SDB throughout Italy. Parents know little about SDB and their complications. The operator satisfaction was associated with the availability of tools for diagnosing SDB.

Practical approach to diagnosis of bland-looking spindle cell lesions of the breast.

The diagnosis of bland-looking spindle cell lesions of the breast is often challenging because there is a close morphological and immunohistochemical overlap among the different entities. The present review will discuss reactive spindle cell nodule/exuberant scar, nodular fasciitis, inflammatory pseudotumor, myofibroblastoma (classic type), lipomatous myofibroblastoma, palisaded myofibroblastoma, benign fibroblastic spindle cell tumor, spindle cell lipoma, fibroma, leiomyoma, solitary fibrous tumor, myxoma, schwannoma/neurofibroma, desmoid-type fibromatosis, dermatofibrosarcoma protuberans, low-grade fibromatosis-like spindle cell carcinoma, inflammatory myofibroblastic tumor and low-grade myofibroblastic sarcoma arising in the breast parenchyma. The pathologist should be aware of each single lesion to achieve a correct diagnosis to ensure patient a correct prognostic information and therapy. Accordingly representative illustrations and morphological/immunohistochemical diagnostic clues will be provided.

Intestinal-type adenocarcinoma of the vagina: clinico-pathologic features of a common tumor with a rare localization.

Intestinal-type adenocarcinoma is a rare primary vaginal carcinoma and considerably more uncommon than metastatic lesions which represent the most frequent malignancy at this anatomic site. Among all malignant tumors, colorectal, breast and female genital tract carcinomas have the tendency to metastasize to the vagina.As morphologic and immunohistochemical features of intestinal-type adenocarcinoma occurring primarily in the vagina are not specific, clinical and radiologic information is crucial to exclude a metastatic lesion.Herein we present a rare case of intestinal-type adenocarcinoma from a villous adenoma, presenting as a polypoid mass in the posterior wall of vaginal introitus of 51-year-old menopausal woman. To the best of our knowledge, only 19 cases of intestinal-type adenocarcinoma of the vagina have been reported in the English literature so far. Notably the origin from a previous villous adenoma has been well documented only in a few cases.

Parotid gland involvement in Heerfordt syndrome: a case report.

Sarcoidosis is a multisystemic granulomatous disease characterized by the presence of noncaseating granulomas, the exact etiology of which is yet to be determined. Most of patients show granulomas located in the lungs or in the related lymph nodes. However, lesions can affect any organ. Noncaseating granulomas are not a pathognomonic sign of sarcoidosis, being observed also in other diseases, therefore the diagnosis is often of exclusion. We report a case of sarcoidosis with parotid gland involvement in the context of a Heerfordt syndrome, discussing about its clinical presentation, pathogenesis, pathology and differential diagnosis with other granulomatous diseases.

Application of intraoperative indocyanine green angiography for CNS tumors: results on the first 100 cases.

PURPOSE: To investigate the application of indocyanine green (ICG) videoangiography during microsurgery for central nervous system (CNS) tumors. METHODS: One hundred patients with CNS tumors who underwent microsurgical resection from December 2006 to December 2008 were retrospectively analyzed. The diagnosis was high grade glioma in 54 cases, low grade in 17 cases, meningioma in 14 cases, metastasis in 12 cases and hemangioblastoma in 3 cases. Overall, ICG was injected intraoperatively 194 times. The standard dose of 25mg of dye was injected intravenously and intravascular fluorescence from within the blood vessels was imaged through an ad hoc microscope with dedicated software (Pentero, Carl Zeiss Co., Oberkochen, Germany). Pre-resection and post-resection arterial, capillary and venous ICG videoangiographic phases were intraoperatively observed and recorded. RESULTS: ICG videangiography allowed for a good evaluation of blood flow in the tumoral and peritumoral exposed vessels in all cases. No side effects due to ICG were observed. CONCLUSIONS: ICG video-angiography is a significant method for monitoring blood flow in the exposed vessels during microsurgical removal of CNS tumors. Pre-resection videoangiography provides useful information on the tumoral circulation and the pathology-induced alteration in surrounding brain circulation. Post-resection examination allows for an immediate check of patency of those vessels that are closely related to the tumor mass and that the surgeon does not want to damage.

Expression of vascular endothelial growth factor receptor-1/-2 and nitric oxide in unruptured intracranial aneurysms.

The biological mechanisms associated with the development and rupture of intracranial aneurysms are not fully understood. To clarify the role of VEGF and the related receptors in the pathophysiology of aneurysm, immunostaining for VEGF, VEGFR1 and VEGFR2 was performed on specimens from six unruptured aneurysms and on two specimens of normal arteries wall as a control. The results were correlated with NO concentration of CSF collected during surgery from 8 patients affected by unruptured aneurysms and in 11 control patients. The immunohistochemical data showed a different pattern of VEGF/VEGFR1/VEGFR2 in aneurysms when compared with control. The results of this preliminary study suggest an imbalance of VEGF, VEGFR1 and VEGFR2, and the interaction of VEGF and NO in the pathophysiology of unruptured aneurysms. Our data support the hypothesis of aneurysm formation associated with a loss of expression of VEGFR1, moderate expression of VEGFR2 and high concentration of nitrate.

Intraoperative microrecordings in the posterior hypothalamus of anaesthetized humans with aggressive behaviour.

Two patients with uncontrollable aggressive behaviour underwent the placement of stimulating leads in the posterior hypothalamus (pHyp). One patient had also multifocal refractory epilepsy. Microrecordings were obtained in both patients during surgery under general anaesthesia. Firing rate, interspike intervals and oscillatory discharge patterns were analysed in 14 neurons. A mean discharge rate of 19 Hz, and oscillatory activity at 7-8 Hz were recorded in the first patient with aggressiveness and epilepsy. In the second patient the mean firing rate was 10 Hz, with evidence of both tonic and random firing patterns. Previous studies in patients with cluster headache showed that a discharge rate around 20 Hz and lack of a specific rhythmic pattern were the most consistent characteristics of neuronal discharge in this area. Our present findings therefore would suggest that the pattern of discharge of neurons in the pHyp should be evaluated with reference to the presence of concurrent pathology.

A case of very long-term appearing drug tolerance to intrathecal baclofen.

A 66-year-old man affected by familial spastic paraplegia since he was 22 developed drug tolerance to intrathecal baclofen after 16 years of treatment A stable dosage of 850 microg/day, achieved after the first two years, appeared to be progressively inadeguate to relief his spasticity. No other evidence of additional diseases or progression of his neurological disease were recognized. The daily dosage was then increased to 1200 microg/day without any decrease in spasticity or improvement in the patient's motor performance. Thus a slow and progressive decrease of the daily dosage was performer by 10% each 15 days while the patient's clinical condition was monitored. The patient reached a complete withdrawal of the baclofen administration experiencing the same spasticity and motor performance he experienced at the beginning of his therapy with intrathecal baclofen in 1991. The patient was then kept on drug holiday for three months without any variation in his clinical picture. A stabilized daily baclofen dosage of 250 microg was then reached to maintain the same improvement of motor performance that the patient had experienced before the onset of drug-tolerance signs. Some cases of drug tolerance to intrathecal baclofen were previously reported but this is an original case of very long-term onset of this phenomenon.

Endoscopic radial artery harvesting for U-clip EC-IC bypass in the treatment of a giant petrous internal carotid artery aneurysm: technical case report.

INTRODUCTION: High-flow extracranial-intracranial (EC-IC) bypass and aneurysm trapping constitutes a well-known surgical solution for internal carotid artery (ICA) aneurysms that are not amenable to clip ligation or endovascular therapy. The advantages of the radial artery (RA) as a conduit for myocardial revascularization have become widely accepted, with a better patency rate than that of the saphenous vein. CASE REPORT: A 66-year-old woman was found to harbour a right giant, partially thrombosed aneurysm of the intrapetrous segment of the internal carotid artery. Endoscopic harvesting of the RA was achieved combining a resterilizable retractor and a vessel sealing system. After neck dissection, the main trunk of the middle cerebral artery (MCA), its branches, and part of the aneurysm were isolated through a right fronto-orbito-zygomatic craniotomy. The external carotid artery, distal to the origin of the facial artery, was chosen in the neck for an end-to-end microanastomosis. The temporal branch of the MCA was selected for an end-to-side microanastomosis with the radial graft using ten U-clips. The total temporary occlusion time was 13 min. The post-operative course was uneventful. CONCLUSION: Endoscopic technique provides improved patient satisfaction, especially in terms of length of the surgical incision, when compared to the conventional approach. Combined with the innovative use of U-clips, this case illustrates how new technologies can simplify ECA-ICA bypass surgery while yielding a better cosmetic and functional outcome.

Hypothalamic stimulation for trigeminal neuralgia in multiple sclerosis patients: efficacy on the paroxysmal ophthalmic pain.

Trigeminal neuralgia is a disorder characterized by paroxysmal pain arising in one or more trigeminal branches; it is commonly reported in multiple sclerosis. In multiple sclerosis patients the ophthalmic branch may be frequently involved and the risks carried by neurosurgical ablative procedures are higher including major adverse effects such as corneal reflex impairment and keratitis. The objective of this works is to assess the role of posterior hypothalamus neuromodulation in the treatment of trigeminal neuralgia in multiple sclerosis patients. Five multiple sclerosis patients suffering from refractory recurrent trigeminal neuralgia involving all three trigeminal branches underwent deep brain stimulation of the posterior hypothalamus. The rationale of this intervention emerges from our earlier success in treating pain patients suffering from trigeminal autonomic cephalalgias. After follow-up periods that ranged from 1 to 4 years after treatment, the paroxysmal pain arising from the first trigeminal branch was controlled, whereas the recurrence of pain in the second and third trigeminal branches necessitated repeated thermorhizotomies to control in pain in two patients after 2 years of follow-up. In conclusion, deep brain stimulation may be considered as an adjunctive procedure for treating refractory paroxysmal pain within the first trigeminal division so as to avoid the complication of corneal reflex impairment that is known to follow ablative procedures.

Costs of hypothalamic stimulation in chronic drug-resistant cluster headache: preliminary data.

In about 20% of chronic cluster headache (CH) cases, drugs may become ineffective. Under these circumstances, steroids and triptans are frequently employed leading to fearful side effects in one and high costs in the other. The direct costs of drug-resistant chronic CH are mainly due to frequent medical consultations and frequent use of expensive drugs. In recent years, hypothalamic stimulation has been employed to treat drug-resistant chronic CH patients suffering multiple daily attacks and long-term results from different centres show a 60% overall benefit. Nine years since the introduction of this technique, we attempt a preliminary analysis of the direct costs of hypothalamic stimulation based on patients treated at our centre. We estimated the following direct costs as follows: cost of neurosurgery plus cost of equipment (electrode, connection and impulse generator = 25,000 euro), cost of hospital admissions in long-term follow-up (2,000 euro per admission), cost of single sumatriptan injection (25 euro). Number of daily sumatriptan injections in the year before and for each year after hypothalamic implantation was obtained from headache diaries. To estimate the saving due to the reduction in sumatriptan consumption following hypothalamic stimulation, we calculated the following for each year of follow-up after surgery: number of sumatriptan injections in the year before surgery minus number of sumatriptan injections in each year, updated to December 2008. In our 19 implanted patients, the costs of neurosurgery plus cost of equipment were 475,000 euro; the costs of hospital admissions during follow up were 250,000 euro. Reduction in sumatriptan consumption resulted in a total saving of 3,573,125 euro. Hence, in our 19 patients, the sumatriptan saving (3,573,125 euro) minus the direct costs due to operation and follow up hospitalisations (475,000 + 250,000) euro is equal to 2,848,125 euro. These preliminary results indicate that hypothalamic stimulation is associated with marked reduction of direct costs in the management of complete drug-resistant chronic CH.

Cluster headache and TACs: rationale for central and peripheral neuromodulation.

Cluster headache, the most severe of primary headache conditions for functional and social impairment it provokes, has been recently the object of a great amount of clinical, physiopathological, surgical and functional neuroradiological studies aimed to uncover the real mechanisms which underlie its disabling manifestations. Refinement of methodological and systematic features of multidisciplinary researches in this field has been allowing for more and more precise delineations of the role of both peripheral and central nervous system's contribution in pathophysiology of the disease. Aim of this manuscript is the report of the present knowledge in the role of the different surgical options in the treatment of drug-resistant cluster headache and Short-lasting Unilateral neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), which take into account their different hypothesized pathological mechanisms and which comprise central nervous system's approach (Deep Brain Stimulation [DBS] and peripheral approach, namely Occipital Nerve Stimulation (ONS) and Vagal Nerve Stimulation (VNS).

Self-closing Nitinol U-Clips for intracranial arterial microanastomosis: a preliminary experience on seven cases.

PURPOSE: To report experience on the use of self-closing nitinol U-Clips for different types of intracranial arterial microanastomosis. METHODS: We treated 7 patients (3 females and 4 males, age ranging from 25 to 68 yo) admitted from November 2005 to January 2008 to the Neurological Institute C. Besta of Milan. One patient had cerebral hypoperfusion and the others a complex intracranial aneurysm. In each patient a bypass procedure was completed by using self-closing Nitinol U-Clips for intracranial arterial microanastomoses. RESULTS: The total time of temporary occlusion was 15.71 +/- 4.386 min. Bypass patency was confirmed intraoperatively by near-infrared indocyanine green videoangiography and microdoppler in each patient. No spasm of the graft was encountered and immediate post-operative bypass patency was confirmed in 6/7 patients. The graft thrombosed in 1 patient with antiphospholipid syndrome. 1 patient died from a massive Subarachnoid Hemorrhage due to rupture of an aneurysm while waiting for an endovascular procedure. In the 5 patients at the last follow-up, long-term patency of the bypass was confirmed and no neurological deficits occurred related to the procedure. CONCLUSION: This is the first report of the use of U-Clips for intracranial microanastomosis. Our data indicated that it is a safe technique, reduces the time taken to perform an anastomosis and the risk of an ischemic complication. Further studies of the longer-term patency of bypass as performed with U-Clips are required.

Endoscopic radial artery harvesting for U-clip high-flow EC-IC bypass: technical report.

INTRODUCTION: Bypass and aneurysm trapping constitute a well-known surgical solution for aneurysms that are not suitable for clipping or coiling. New techniques are available that make EC-IC bypass procedures easier, safer and, possibly, less invasive. The nitinol self-closing U-Clip device (Medtronic, Inc., Minneapolis) has been designed to facilitate the interrupted suture technique by eliminating the need for suture management, knot tying, and surgical assistance. MATERIALS AND METHODS: We present two consecutive U-clip bypass procedures in which the radial artery graft was harvested endoscopically. RESULTS: This novel bypass technique employs endoscopy to minimise arm injury due to radial artery harvesting and self-closing U-clips to simplify the intracranial micro-anastomosis and reduce the temporary occlusion time. Angiography confirmed bypass patency in all patients. DISCUSSION: Combined with the innovative use of U-clips, these two examples illustrate how new technologies can simplify EC-IC bypass surgery while yielding a better cosmetic and functional outcome.

Use of self-closing U-clips for dural repair in mini-invasive surgery for herniated disc.

OBJECT: The feasibility of a new technique of dural repair (self-closing U-clips) in mini-invasive surgery for herniated disk is demonstrated in this case report. MATERIALS AND METHODS: A 44-year-old male patient underwent lumbar microdiscectomy at out Institute, with subsequent dural leak as surgical complication; the dural leak re-appeared even after a second intervention in which we used muscle and dural graft and fibrin glue to repair the leak. We then decided to employ self-closing nitinol- U-clip to achieve primary dural closure. RESULTS: After the intervention the patient no more presented signs or symptoms due to the unintended durotomy, and the postoperative course was uneventful. CONCLUSION: Self-closing nitinol U-clips (Medtronic, Inc., Minneapolis) can be used for closing a dural tear through a mini-invasive approach that could make a conventional microsuturing technique very difficult.

Results by motor cortex stimulation in treatment of focal dystonia, Parkinson's disease and post-ictal spasticity. The experience of the Italian Study Group of the Italian Neurosurgical Society.

Extradural motor cortex stimulation has been employed in cases of Parkinson's disease (PD), fixed dystonia (FD) and spastic hemiparesis (SH) following cerebral stroke. Symptoms of PD are improved by EMCS: results were evaluated on the basis of the UPDRS and statistically analysed. In PD EMCS is less efficacious than bilateral subthalamic nucleus (STN) stimulation, but it may be safely employed in patients not eligible for deep brain stimulation (DBS). The most rewarding effect is the improvement, in severely affected patients, of posture and gait. FD, unresponsive to bilateral pallidal stimulation, has been relieved by EDMS. In SH reduction of spasticiy by EMCS allows improvement of the motor function.

Lessons from 8 years' experience of hypothalamic stimulation in cluster headache.

Neuroimaging studies in cluster headache (CH) patients have increased understanding of attack-associated events and provided clues to the pathophysiology of the condition. They have also suggested stimulation of the ipsilateral posterior inferior hypothalamus as a treatment for chronic intractable CH. After 8 years of experience, stimulation has proved successful in controlling the pain attacks in almost 60% of chronic CH patients implanted at various centres. Although hypothalamic implant is not without risks, it has generally been performed safely. Implantation affords an opportunity to perform microrecordings of individual posterior hypothalamic neurons. These studies are at an early stage, but suggest the possibility of identifying precisely the target site by its electrophysiological characteristics. Autonomic studies of patients undergoing posterior hypothalamic stimulation provide further evidence that long-term stimulation is safe, revealing that it can cause altered modulation of the mechanisms of orthostatic adaptation without affecting the baroreflex, cardiorespiratory interactions or efferent sympathetic and vagal functions. Chronically stimulated patients have an increased threshold for cold pain at the site of the first trigeminal branch ipsilateral to the stimulated side; when the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, suggesting that long-term stimulation is required to induce sensory and nociceptive changes. Posterior inferior hypothalamic stimulation is now established as a treatment for many chronic CH patients. The technique is shedding further light on the pathophysiology of the disease, and is also providing clues to functioning of the hypothalamus itself.