Endoscopic management of frontal sinus diseases after frontal craniotomy: a case series and review of the literature.

PURPOSE: To evaluate frontal sinus complications developed after previous external craniotomies requiring frontal sinus reconstruction and their treatment with an endoscopic approach. METHODS: We retrospectively evaluated 22 patients who referred to Sant'Orsola-Malpighi University Hospital and Bellaria Hospital (Bologna, Italy) between 2005 and 2017. All patients presented with frontal sinus disease after frontal craniotomy with sinus reconstruction performed to treat various pathological conditions. We reported our experience in the endoscopic management of such complications and we reviewed the current literature concerning the endoscopic treatment of these conditions. RESULTS: In total, 14 frontal mucoceles, 4 cases of chronic frontal sinusitis, 2 mucopyoceles and 2 fungus ball of the frontal sinus were identified. Endoscopic surgical treatment included 7 DRAF IIa, 1 DRAF IIb, 11 DRAF III and 3 DRAF IIc (modified DRAF III) approaches. The success rate of the surgical procedure was 86% (19/22 patients). Recurrence of the initial pathology occurred in three patients (14%) requiring a conversion of previous frontal sinusotomy into a DRAF III sinusotomy. CONCLUSION: Frontal sinusopathy can be a long-term complication following craniotomies and may lead to potentially severe pathological conditions, such as mucoceles and frontal sinus inflammation. Its management is still debated and requires recovery of the patency of nasal-frontal route. Our study confirms that the endoscopic endonasal approach may offer a valid solution with low morbidity avoiding re-opening of the craniotomic access. For selected cases, endoscopic approach could also be performed simultaneously to craniotomy as a combined surgery to reduce the risk of short- and long-term complications. Long-term follow-up is mandatory in patients with a history of opened and reconstructed frontal sinus and should include imaging and endoscopic outpatient evaluation.

Results and predictors of outcome of endoscopic endonasal surgery in Cushing's disease: 20-year experience of an Italian referral Pituitary Center.

PURPOSE: To assess outcomes and predictors of early and long-term remission in patients with Cushing's disease (CD) due to ACTH-secreting adenomas treated via endoscopic endonasal approach (EEA). METHODS: This is a retrospective study. Consecutive patients operated for CD from 1998 to 2017 in an Italian referral Pituitary Center were enrolled. Clinical, radiological, and histological data at enrollment and follow-up were collected. RESULTS: 151 patients (107 F) were included; 88.7% were naïve for treatment, 11.3% had been treated surgically and 11.2% medically. At pre-operative magnetic resonance imaging (MRI), 35 had a macroadenoma and 80 a microadenoma, while tumor was undetectable in 36 patients. Mean age at surgery was 41.1 ± 16.6 years. Diagnosis was confirmed histologically in 82.4% of the cases. Patients with disease persistence underwent second surgery and/or medical and/or radiation therapy. Mean follow-up was 92.3 ± 12.0 (range 12-237.4) and median 88.2 months. Remission rate was 88.1% after the first surgery and 90.7% at last follow-up. One patient died of pituitary carcinoma. Post-surgical cortisol drop (p = 0.004), tumor detection at MRI (p = 0.03) and size < 1 cm (p = 0.045) increased the chance of disease remission; cavernous sinus invasion was a negative predictor of outcome (p = 0.002). Twenty-seven patients developed diabetes insipidus and 18 hypopituitarism. Surgery repetition increased the risk of hypopituitarism (p = 0.03), but not of other complications, which included epistaxis (N = 2), cerebrospinal fluid leakage (1), pneumonia (3), myocardial infarction (1), and pulmonary embolisms (2). CONCLUSIONS: Selective adenomectomy via EEA performed by experienced surgeons, supported by a multidisciplinary dedicated team, allows long-term remission in the vast majority of CD patients with low complication rate.

Exploiting Bacterial Pathways for BBB Crossing with PLGA Nanoparticles Modified with a Mutated Form of Diphtheria Toxin (CRM197): In Vivo Experiments.

Drugs can be targeted to the brain using polymeric nanoparticles (NPs) engineered on their surface with ligands able to allow crossing of the blood-brain barrier (BBB). This article aims to investigate the BBB crossing efficiency of polymeric poly lactide-co-glycolide (PLGA) NPs modified with a mutated form of diphtheria toxin (CRM197) in comparison with the results previously obtained using PLGA NPs modified with a glycopeptide (g7-NPs). Different kinds of NPs, covalently coupled PLGA with different fluorescent probes (DY405, rhodamine-B base and DY675) and different ligands (g7 and CRM197) were tested in vivo to assess their behavior and trafficking. The results highlighted the possibility to distinguish the different kinds of simultaneously administered NPs and to emphasize that CRM-197 modified NPs and g7-NPs can cross the BBB at a similar extent. The analysis of BBB crossing and of the neuronal tropism of CRM197 modified NPs, along with their BBB crossing pathways were also developed. In vivo pharmacological studies performed on CRM197 engineered NPs, loaded with loperamide, underlined their ability as drug carriers to the CNS.

Clinical predictors of fever in stroke patients: relevance of nasogastric tube.

OBJECTIVES: Fever frequently occurs in stroke patients and worsens their prognosis. However, only few studies have assessed the determinants of fever in acute stroke, and no study has specifically addressed the possible prediction of the development of fever. MATERIALS AND METHODS: This investigation included 536 patients with acute stroke and a body temperature <=37°C during the first 24 h of stay. Ninety-two of them (17.2%) subsequently developed fever (defined as a temperature >=37.5°C starting after 24 h). Among the clinical variables available during the first 24 h from admission, those predictive of the subsequent appearance of fever were searched for. One hundred further patients had a temperature >37°C during the first 24 h. RESULTS: In univariate analysis, many variables were predictive of the subsequent development of fever, but in multivariate analysis, only the following four predictors remained significant (odds ratio [95% confidence interval], P value): nasogastric tube (4.0 [2.2-7.4], <0.0001), atrial fibrillation (2.3 [1.4-3.8], 0.001), total anterior circulation syndrome (2.0 [1.2-3.5], 0.01), and urinary catheter (1.9 [1.1-3.3], 0.01). Among the 52 (9.7%) patients with three or four predictors, 31 (59.6%) subsequently developed fever. In addition, the factors independently associated with a temperature >37°C during the first 24 h were as follows: National Institutes of Health Stroke Scale (P < 0.0001), hemorrhagic stroke (P = 0.0008), atrial fibrillation (P = 0.002), and total parenteral nutrition (P = 0.03). CONCLUSIONS: In patients with acute stroke, four clinical variables were found to be independently associated with the risk of developing fever and, of them, nasogastric tube was the strongest and most significant one.

A comparison of risk factors as predictors of cardiovascular and non-cardiovascular mortality in the elderly people--relevance of N-terminal pro-B-type natriuretic peptide and low systolic blood pressure.

BACKGROUND: Many risk factors are known to predict ischaemic events and mortality in the elderly people, but their ranking of importance remains uncertain. This study was designed to identify and compare the main predictors of total mortality (TM), cardiovascular mortality (CVM) and non-cardiovascular mortality (NCVM) in older adults. METHODS: Nine hundred and seventy-nine community resident adults aged ≥ 65 years, free of previous heart failure and cardiovascular events, participated in the study. The univariate and multivariate (Cox regression) relationships of baseline cardiovascular risk factors, treatments and laboratory data with TM, CVM and NCVM were assessed after a median follow up of 6.7 years. RESULTS: Overall, there were 104 deaths (30 because of CVM and 74 to NCVM). In multivariate analysis, the following factors remained independently associated with mortality: NT pro-B-type natriuretic peptide (NT-proBNP) upper quintile (≥ 237 pg/ml for men, ≥ 280 pg/ml for women): hazard ratio (HR) vs. the rest of the population (95% confidence interval) 2.34 (1.52-3.60), p < 0.001 for TM; HR 5.41 (2.32-12.65), p < 0.001 for CVM; systolic blood pressure lower quintile (≤ 130 mmHg): HR 3.06 (1.80-5.21), p < 0.001 for NCVM; diabetes: HR 2.46 (1.29-4.72), p = 0.007 for NCVM; erythrocyte sedimentation rate (ESR) upper decile (≥ 41 mm/h): HR 2.33 (1.16-4.69), p = 0.02 for NCVM; platelet count lower quintile (≤ 177 × 10(9) /l): HR 2.09 (1.20-3.64), p = 0.009 for NCVM; ever-smoker status: HR 2.08 (1.23-3.52), p = 0.007 for NCVM. CONCLUSIONS: In elderly community dwellers, NT-proBNP was the strongest predictor of TM and CVM, while especially low systolic blood pressure, together with diabetes, ESR, reduced platelet count and ever-smoker status, were the main predictors of NCVM.

Extended endoscopic transplanum-transtuberculum approach for pituitary adenomas.

Few pituitary adenomas require removal through a transcranial route. This may be associated with more significant morbidity and mortality, compared to the transsphenoidal approach. An endoscopic, extended, transplanum-transtuberculum approach (ETTA) in selected pituitary adenomas may offer an alternative to the transcranial route. We describe our technique and experience of ETTA in pituitary adenomas over 10 years. Between 2000 and 2010, we performed 700 endoscopic endonasal procedures for pituitary adenomas. Nineteen patients (13 men; mean age, 48 years; range, 22-76 years) underwent 22 ETTAs. Thirteen patients had non-functioning adenomas. Three tumor groups were identified: (1) tumors developing in or around the pituitary stalk; (2) tumours with sub- frontal extension and (3) tumours with a major extrasellar component. Mean follow-up was 37 months (range 6-72 months). Gross total resection was achieved in 11 procedures (no recurrences), with partial tumour resection in 11 procedures. Of the 12 patients with visual symptoms, ten improved. Of eight patients with hormonal hypersecretion four were cured. Complications included CSF leak (14%), haemorrhage (9%), hemiplegia (5%). There were no mortalities. Experience using the ETTA for pituitary adenomas is limited because it is indicated in highly selected cases (3.1% of our series). An absolute indication is represented by ectopic secreting pituitary stalk/peri-stalk adenomas. ETTA is a useful option in midline frontal adenomas and adenomas with a major extrasellar component, but has a higher morbidity than that seen in the standard transsphenoidal approach. A study comparing ETTA versus transcranial resection is highly desirable.

MR Brain Screening in ADPKD Patients : To Screen or not to Screen?

BACKGROUND: Adult polycystic kidney disease (ADPKD) still represents a major cause of renal failure and intracranial aneurisms (IA) have a higher prevalence in ADPKD than in the general population. Current guidelines suggest performing brain MRI only in the subjects with a positive familiar history of IAs or subarachnoid hemorrhage (SAH). This is a retrospective case-control analysis to evaluate the usefulness of a MR screening program in ADPKD patients. METHODS: We retrospectively analyzed all ADPKD patients followed in our outpatient clinic between 2016 and 2019 who underwent a brain MRI screening. We evaluated the presence of IAs and others brain abnormalities and compared our results with a non-ADPKD population (n = 300). We performed univariate and multivariate regression analysis to evaluate if general and demographic features, laboratory findings, clinical parameters and genetic test results correlated with IAs or other brain abnormalities presence. RESULTS: Among the patients evaluated 17 out of 156 (13.6%) ADPKD patients had IAs, compared to 16 out of 300 (5.3%) non-ADPKD controls (p < 0.005). Considering ADPKD patients presenting IAs, 12 (70.6%) had no family history for IAs or SAH. Genetic analysis was available for 97 patients: in the sub-population with IAs, 13 (76.5%) presented a PKD1 mutation and none a PKD2 mutation. We found that arachnoid cysts (AC) (p < 0.001) and arterial anatomical variants (p < 0.04) were significantly more frequent in ADPKD patients. CONCLUSION: In our population ADPKD patients showed a higher prevalence of IAs, AC and arterial variants compared to non-ADPKD. Most of the IAs were found in patients presenting a PKD1 mutation. We found a significant number of alterations even in those patients without a family history of IAs or SAH. The practice of submitting only patients with familial IAs or kidney transplantation candidates to MRI scan should be re-evaluated.

A simple scoring system for outcome prediction of ischemic stroke.

OBJECTIVES: According to most existing models, a computer is usually needed for predicting stroke outcome. Our purpose was to construct a simple and reliable prognostic scale not requiring the use of a calculating machine. MATERIALS AND METHODS: The scale [the Bologna Outcome Algorithm for Stroke (BOAS)] was obtained in 221 patients with ischemic stroke not undergoing thrombolysis and was then validated in a test group of 100 different patients. Outcome was assessed at 9 months as the number of dependent or dead patients (modified Rankin scale - mRS > 2). RESULTS: By a preliminary systematic univariate analysis, 25 of 415 baseline variables were found to be associated with a mRS > 2 independently of stroke severity and age. Subsequent multivariable analyses led to a final model based on five dichotomous risk factors (RF): National Institutes of Health Stroke Scale score ≥10, age ≥78, need of urinary catheter, oxygen administration, and persistence of upper limb paralysis at discharge from stroke unit. The patients with two or more RF (53%) had a mRS > 2 in 91% of cases and were dead in 42% of cases. With 0-1 RF, the two percentages were 24% and 2%, respectively (overall accuracy of prediction 83.9%, area under ROC curve [AUC] 0.891). In the test group, the accuracy was 79.0% and the AUC was 0.839. CONCLUSIONS: The need of urinary catheter, oxygen administration, and persistence of upper limb paralysis, together with stroke severity and advanced age, allow a simple and accurate prediction of dependency or death after ischemic stroke.

Stacking interactions in denaturation of DNA fragments.

A mesoscopic model for heterogeneous DNA denaturation is developed in the framework of the path integral formalism. The base pair stretchings are treated as one-dimensional, time-dependent paths contributing to the partition function. The size of the paths ensemble, which measures the degree of cooperativity of the system, is computed versus temperature consistently with the model potential physical requirements. It is shown that the ensemble size strongly varies with the molecule backbone stiffness providing a quantitative relation between stacking and features of the melting transition. The latter is an overall smooth crossover which begins from the adenine-thymine-rich portions of the fragment. The harmonic stacking coupling shifts, along the T -axis, the occurrence of the multistep denaturation but it does not change the character of the crossover. The methods to compute the fractions of open base pairs versus temperature are discussed: by averaging the base pair displacements over the path ensemble, we find that such fractions signal the multisteps of the transition in good agreement with the indications provided by the specific heat plots.

Age dependency of regional impedance indices regardless of clinical stage in patients with cirrhosis of the liver.

PURPOSE: To prospectively assess if ageing itself induces modifications of the impedance indices (resistance and pulsatility indexes) of hepatic, splenic, superior mesenteric and renal arteries in patients with liver cirrhosis. MATERIALS AND METHODS: 78 consecutive patients with cirrhosis (41 males, 37 females, Child-Pugh score 7 [range 5 - 12]) were studied by colour-Doppler ultrasound. The resistance index (RI) and pulsatility index (PI) were determined in the main hepatic artery, intraparenchymal branches of hepatic, splenic, and renal arteries, and superior mesenteric artery; clinical data were simultaneously collected. Logistic regression analysis was performed to assess the relative impact of age, severity of liver disease and other relevant variables on the increase of impedance indices. Linear regression analysis was used to identify a coefficient to adjust RIs and PIs to age. RESULTS: Resistance and pulsatility indices of all the vessels studied except of the superior mesenteric artery showed a direct correlation with age (e. g. splenic artery RI: R = 0.520, p < 0.0001), and correlated most strongly with Child-Pugh score (e. g. right renal artery PI: R = 0.462, p < 0.0001). Age was associated independently with increased PI and RI in hepatic, splenic and renal arterial districts. In these vessels, the RI threshold of normality can be adjusted to the decade of age adding a correction of 0.03. CONCLUSION: Ageing itself induces an increase of hepatic, splenic and renal impedance indices in cirrhotic patients. The threshold of normality for these indices in cirrhosis should be adjusted according to the patients' age.

Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre.

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas' score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

New abdominal collaterals at ultrasound: a clue of progression of portal hypertension.

BACKGROUND: Abdominal ultrasound can detect non-invasively the presence of abdominal portal-systemic collaterals in patients with liver cirrhosis. Abdominal portal-systemic collaterals may be protective from the formation and growth of oesophageal varices, but available data are inconclusive. AIM: We aimed at investigating the relationship between abdominal portal-systemic collaterals and variceal formation and growth. METHODS: We studied 126 cirrhotic patients without (n=43) or with small (n=83) oesophageal varices who entered a protocol of serial ultrasonographic and endoscopic examinations for a median of 55 months. Presence and kind of abdominal portal-systemic collaterals was recorded on first ultrasonography and on each control thereafter. RESULTS: At inclusion, abdominal portal-systemic collaterals were found in 19/43 patients without varices and in 23/83 patients with small varices (NS). There was no difference in variceal formation and growth between patients with and without abdominal portal-systemic collaterals at inclusion. However, patients developing new abdominal portal-systemic collaterals during follow-up had a significantly higher rate of variceal formation (56.2% vs. 22.2%; p=0.024) and growth (52.9% vs. 30.6%; p=0.041) compared with patients with unchanged ultrasonography. CONCLUSIONS: Abdominal collaterals are not protective from the formation or growth of oesophageal varices. Conversely, new abdominal portal-systemic collaterals emergence is a non-invasive clue of formation and progression of varices. Therefore, endoscopy is probably indicated whenever new abdominal portal-systemic collaterals are detected in cirrhotic patients.

Selective disarrangement of the rostral telencephalic cholinergic system in heterozygous reeler mice.

Reelin (RELN) is a key molecule for the regulation of neuronal migration in the developing CNS. The reeler mice, which have spontaneous autosomal recessive mutation in the RELN gene, reveal multiple defects in brain development. Morphological, neurochemical and behavioral alterations have been detected in heterozygous reeler (HR) mice, suggesting that not only the presence, but also the level of RELN influences brain development. Several studies implicate an involvement of RELN in the pathophysiology of neuropsychiatric disorders in which an alteration of the cholinergic cortical pathways is implicated as well. Thus, we decided to investigate whether the basal forebrain (BF) cholinergic system is altered in HR mice by examining cholinergic markers at the level of both cell body and nerve terminals. In septal and rostral, but not caudal, basal forebrain region, HR mice exhibited a significant reduction in the number of choline acetyltransferase (ChAT) immunoreactive (ir) cell bodies compared with control mice. Instead, an increase in ChAT ir neurons was detected in lateral striatum. This suggests that an alteration in ChAT ir cell migration which leads to a redistribution of cholinergic neurons in subcortical forebrain regions occurs in HR mice. The reduction of ChAT ir neurons in the BF was paralleled by an alteration of cortical cholinergic nerve terminals. In particular, the HR mice presented a marked reduction of acetylcholinesterase (AChE) staining accompanied by a small reduction of cortical thickness in the rostral dorsomedial cortex, while the density of AChE staining was not altered in the lateral and ventral cortices. Present results show that the cholinergic basalo-cortical system is markedly, though selectively, impaired in HR mice. Rostral sub-regions of the BF and rostro-medial cortical areas show significant decreases of cholinergic neurons and innervation, respectively.

Site and type of craniopharyngiomas impact differently on 24-hour circadian rhythms and surgical outcome. A neurophysiological evaluation.

This study aimed to quantify 24h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.

Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon.

BACKGROUND: In HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma (HCC), the time to HCC recurrence and the effects of sustained viral eradication (SVR) by interferon (IFN)-based or IFN-free regimens on HCC recurrence remain unclear. AIM: To perform an indirect comparison of time to recurrence (TTR) in patients with successfully treated early HCC and active HCV infection with those of patients with SVR by IFN-based and by IFN-free regimens. METHODS: We evaluated 443 patients with HCV-related cirrhosis and Barcelona Clinic Liver Cancer Stage A/0 HCC who had a complete radiological response after curative resection or ablation. Active HCV infection was present in 328, selected from the Italian Liver Cancer group cohort; 58 patients had SVR achieved by IFN-free regimens after HCC cure, and 57 patients had SVR achieved by IFN-based regimens after HCC cure. Individual data of patients in the last two groups were extracted from available publications. RESULTS: TTR by Kaplan-Meier curve was significantly lower in patients with active HCV infection compared with those with SVR both by IFN-free (P = 0.02) and by IFN-based (P < 0.001) treatments. TTR was similar in patients with SVR by IFN-free or by IFN-based (P = 0.49) strategies. CONCLUSION: In HCV-infected, successfully treated patients with early HCC, SVR obtained by IFN-based or IFN-free regimens significantly reduce tumour recurrence without differences related to the anti-viral strategy used.

Octreotide in the outpatient therapy of cirrhotic chylous ascites: a case report.

Chylous ascites is a rare complication of liver cirrhosis associated with a poor short-term prognosis. We report the case of an 80-year-old male cirrhotic patient with refractory chylous ascites associated with portal hypertension. He was treated with total parenteral nutrition but chylous ascites relapsed at suspension. Patient was put on long-term subcutaneous octreotide (100 microg t.i.d.) as an outpatient. The treatment was well tolerated and led to clinical improvement, markedly reducing the need of total paracentesis and the amount of ascites. Octreotide was stopped after 6 months, and massive ascites did not relapse. After 1 year the patient was alive, with no need of paracentesis. Octreotide therapy should be considered in patients with cirrhosis and chylous ascites to simplify the outpatient management of the disease.

Wiring and volume transmission in the central nervous system: the concept of closed and open synapses.

During the past two decades, several revisions of the concepts underlying interneuronal communication in the central nervous system (CNS) have been advanced. Our group has proposed to classify intercellular communication in the CNS under two general frames: 'wiring' (WT) and 'volume' transmission (VT). WT is characterized by a single 'transmission channel' made by cellular (neuronal or glial) structures and with a region of discontinuity not larger than a synaptic cleft. VT is characterized by the diffusion from a cell source (neuronal or glial) of chemical and electrical signals in the extracellular fluid (ECF) for a distance larger than the synaptic cleft Based on morphological and functional characteristics, and in light of the distinction proposed, six main modes of intercellular communication can be recognized in the CNS: gap-junction, membrane juxtaposition, and closed synapse (which represent WT-type modes of communication); open synapse, paracrine transmission and endocrine-like transmission (which represent VT-type modes of communication). Closed and open synapses are distinguished on the basis of the sealing of the signal within or the leakage of the signal outside the synapse Intra-synaptic restriction or extra-synaptic diffusion of transmitters are insured by a number of anatomical arrangements (e.g. glial ensheathment of synapse, size of the synaptic cleft) and functional mechanisms (e.g. density and location of transmitter re-uptake sites and metabolic enzymes). Some central synapses can switch from closed to open state and vice versa, e.g. by changing the amount of transmitter released. Finally, a synapse containing several transmitters can work as an open synapse for one transmitter and as a closed synapse for another.

In vivo chronic nicotine exposure differentially and reversibly affects upregulation and stoichiometry of α4ß2 nicotinic receptors in cortex and thalamus.

Studies with heterologous expression systems have shown that the α4ß2 nicotinic acetylcholine receptor (nAChR) subtype can exist in two stoichiometries (with two [(α4)2(ß2)3] or three [(α4)3(ß2)2] copies of the α subunit in the receptor pentamer) which have different pharmacological and functional properties and are differently regulated by chronic nicotine treatment. However, the effects of nicotine treatment in vivo on native α4ß2 nAChR stoichiometry are not well known. We investigated in C57BL/6 mice the in vivo effect of 14-day chronic nicotine treatment and subsequent withdrawal, on the subunit expression and ß2/α4 subunit ratio of (3)H-epibatidine labeled α4ß2*-nAChR in total homogenates of cortex and thalamus. We found that in basal conditions the ratio of the ß2/α4 subunit in the cortex and thalamus is different indicating a higher proportion in receptors with (α4)2(ß2)3 subunit stoichiometry in the thalamus. For cortex exposure to chronic nicotine elicited an increase in receptor density measured by (3)H-epibatidine binding, an increase in the α4 and ß2 protein levels, and an increase in ß2/α4 subunit ratio, that indicates an increased proportion of receptors with the (α4)2(ß2)3 stoichiometry. For thalamus we did not find a significant increase in receptor density, α4 and ß2 protein levels, or changes in ß2/α4 subunit ratio. All the changes elicited by chronic nicotine in cortex were transient and returned to basal levels with an average half-life of 2.8 days following nicotine withdrawal. These data suggest that chronic nicotine exposure in vivo favors increased assembly of α4ß2 nAChR containing three ß2 subunits. A greater change in stoichiometry was observed for cortex (which has relatively low basal expression of (α4)2(ß2)3 nAChR) than in thalamus (which has a relatively high basal expression of (α4)2(ß2)3 nAChR).

Comparison between alcohol- and hepatitis C virus-related hepatocellular carcinoma: clinical presentation, treatment and outcome.

BACKGROUND: Hepatitis C virus (HCV) and alcohol abuse are the main risk factors for hepatocellular carcinoma (HCC) in Western countries. AIM: To investigate the role of alcoholic aetiology on clinical presentation, treatment and outcome of HCC as well as on each Barcelona Clinic Liver Cancer (BCLC) stage, as compared to HCV-related HCCs. METHODS: A total of 1642 HCV and 573 alcoholic patients from the Italian Liver Cancer (ITA.LI.CA) database, diagnosed with HCC between January 2000 and December 2012 were compared for age, gender, type of diagnosis, tumour burden, portal vein thrombosis (PVT), oesophageal varices, liver function tests, alpha-fetoprotein, BCLC, treatment and survival. Aetiology was tested as predictor of survival in multivariate Cox regression models and according to HCC stages. RESULTS: Cirrhosis was present in 96% of cases in both groups. Alcoholic patients were younger, more likely male, with HCC diagnosed outside surveillance, in intermediate/terminal BCLC stage and had worse liver function. After adjustment for the lead-time, median (95% CI) overall survival (OS) was 27.4 months (21.5-33.2) in alcoholic and 33.6 months (30.7-36.5) in HCV patients (P = 0.021). The prognostic role of aetiology disappeared when survival was assessed in each BCLC stage and in the Cox regression multivariate models. CONCLUSIONS: Alcoholic aetiology affects survival of HCC patients through its negative effects on secondary prevention and cancer presentation but not through a greater cancer aggressiveness or worse treatment result. In fact, survival adjusted for confounding factors was similar in alcoholic and HCV patients.

Years of life that could be saved from prevention of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) causes premature death and loss of life expectancy worldwide. Its primary and secondary prevention can result in a significant number of years of life saved. AIM: To assess how many years of life are lost after HCC diagnosis. METHODS: Data from 5346 patients with first HCC diagnosis were used to estimate lifespan and number of years of life lost after tumour onset, using a semi-parametric extrapolation having as reference an age-, sex- and year-of-onset-matched population derived from national life tables. RESULTS: Between 1986 and 2014, HCC lead to an average of 11.5 years-of-life lost for each patient. The youngest age-quartile group (18-61 years) had the highest number of years-of-life lost, representing approximately 41% of the overall benefit obtainable from prevention. Advancements in HCC management have progressively reduced the number of years-of-life lost from 12.6 years in 1986-1999, to 10.7 in 2000-2006 and 7.4 years in 2007-2014. Currently, an HCC diagnosis when a single tumour <2 cm results in 3.7 years-of-life lost while the diagnosis when a single tumour ≥ 2 cm or 2/3 nodules still within the Milan criteria, results in 5.0 years-of-life lost, representing the loss of only approximately 5.5% and 7.2%, respectively, of the entire lifespan from birth. CONCLUSIONS: Hepatocellular carcinoma occurrence results in the loss of a considerable number of years-of-life, especially for younger patients. In recent years, the increased possibility of effectively treating this tumour has improved life expectancy, thus reducing years-of-life lost.