Outcome and diagnostic reproducibility of the thyroid cytology "indeterminate categories" SIAPEC/SIE 2014 in a consecutive series of 302 cases.

PURPOSE: The clinical impact of the SIAPEC/SIE 2014 classification for thyroid cytology has been addressed in few studies that evaluated the malignancy rate and the relative prevalence of each category. No study analyzed its intra-observer and inter-observer reproducibility, so far. METHODS: We retrospectively collected all "indeterminate" lesions diagnosed before (2011-2014) and after (2015-2018) the application of the SIAPEC/SIE 2014 classification at our Institution. Their relative malignancy risks were calculated based on available histological diagnoses. Cytological and clinical features of TIR3A were compared with the surgical outcome. Finally, a large set of samples was re-evaluated in blind of the original cytological and histological diagnoses by two pathologists, independently. RESULTS: The prevalence of "indeterminate" diagnoses increased in years 2015-2018 (302/1482, 21% with 14% of TIR3A and 7% TIR3B categories) compared to years 2011-2014 (261/1680, 16%). Surgery was performed in 27% TIR3A and in 97% TIR3B cases. Malignancy rates were 40% for TIR3B and 17% for TIR3A, but were greatly influenced by the adoption of the WHO 2017 re-classification of encapsulated follicular-patterned lesions (decreasing to 28% and 6%, respectively). No criteria except for tumor size were associated to malignancy in TIR3A category. Intra-observer agreement of the experienced pathologist was 122/141 (86%), whereas inter-observer agreement between the expert and in-training pathologist was 95/141 (67%). CONCLUSIONS: In this real-life experience, the sub-classification of TIR3A and TIR3B slightly increased the overall prevalence of "indeterminate" diagnoses. Malignancy rates were higher than estimated for both TIR3A and TIR3B categories. Agreement among observers highly depended on pathologist's training.

Clinical and MRI Predictors of Conversion From Mild Behavioural Impairment to Dementia.

OBJECTIVE: As an analogy with mild cognitive impairment (MCI), the mild behavioral impairment (MBI) construct has been proposed as a diagnostic label for those presenting late-onset behavioral symptoms. To date, however, the clinical, cognitive, and structural imaging features associated with an increased risk of conversion from MBI to dementia are poorly understood. METHODS: We retrospectively analyzed the cognitive performance and structural brain MRI of 113 subjects, with a clinical follow-up of at least 4 years available. Subjects were randomly assigned to a Group A (56 subjects; age: 65.4 ± 7.9 years, 15 females, MMSE score: 28.4 ± 2.3)) or to a Group B (57 subjects, age: 66.6 ± 6.4, 17 females, MMSE score: 28.0 ± 1.4). In the Group A, cognitive and structural variables were compared between converters (at 4 years) and nonconverters and then verified in the Group B group. RESULTS: In the Group A, 14 patients converted to behavioral-variant of frontotemporal dementia (bv-FTD) and 4 to Alzheimer's Disease (AD). Converters presented at baseline lower executive function scores and total Theory of Mind (ToM scores), as well as more severe focal frontal atrophy. In the Group B, 13 subjects converted to bv-FTD and none to AD. The combination of the variables identified in the Group A significantly (p <0.001) discriminated between converters and nonconverters in the Group B with a sensitivity of 0.615 and a specificity of 1 (total accuracy 91.22%). CONCLUSION: The combined presence of executive deficit, impaired ToM, and presence of isolated frontal atrophy was associated with risk of progression from MBI to a clinically evident neurodegenerative condition, mainly bv-FTD, over a 4-year period.

Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.

BACKGROUND AND PURPOSE: Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients' management was studied, focusing on the subgroup of Ab-negative-AE. METHODS: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). RESULTS: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second-line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first-line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00-1.04). CONCLUSIONS: In-house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab-positive-AE underestimation. Notwithstanding this limitation, our findings suggest that Ab-negative-AE and Ab-positive-AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab-negative-AE patients risk worse responses due to delayed and less aggressive treatments.

Recreational Boating in Ligurian Marine Protected Areas (Italy): A Quantitative Evaluation for a Sustainable Management.

Recreational boating is an important economic activity that can also represent a powerful source of interference for biological communities. The monitoring of the recreational boating in all Marine Protected Areas (MPAs) within the Liguria region was conducted in the 2010 summer season and it allowed to obtain information not provided by any official institution. The collaboration of geographically different MPAs in Liguria has led to the implementation of a monitoring framework of recreational boating, and this has made it possible to develop uniform management strategies for all the Ligurian marine parks. This study identifies the optimal number of boats for each MPAs, the number of boats that can anchor in the various parks without creating any impact on the biocenosis of merit, providing a first characterization of recreational boating in Liguria during the high touristic season and providing management recommendation to each MPAs. Generally, the Ligurian MPAs do not present critical situations, the number of boats in each MPA being below the optimal number, with the exception of Portofino MPA, where in the 12.5 % of monitored days more than 220 boats were counted and the mean density for weekend is 1.19 no boats/ha (4 times higher than weekday). The results confirm the dependence of the boats peaking from the holidays and the months of the summer, but also it highlights other factors that can contribute in the choice of the boaters.

Bendamustine-rituximab (BR) combined therapy for treatment of immuno-mediated neuropathies associated with hematologic malignancy.

In chronic polyneuropathies associated with hematologic malignancy (HM) the optimal treatment management is primarily focused on the HM, but the parallel response of the neuropathy is still unclear. Rituximab is a recognized therapeutic choice in anti-MAG antibody polyneuropathy, that might be useful also in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with HM. The efficacy of immunochemotherapy, which is the standard approach to malignant lymphoproliferative diseases, has been poorly investigated in polyneuropathies. We describe a six-months combined bendamustine-rituximab (BR) treatment in nine patients affected by CIDP or paraproteinemic IgM neuropathies with antibodies to peripheral nerve antigens in course of malignant HM. All patients had a long-lasting response with an average relapse free-survival (RFS) time of 31.5 months. Clinical improvement was evident at 6 months from the beginning of therapy, even earlier in 6/9 patients (<2 months). Two patients dramatically improved the disabling attitudinal and intentional tremor and pathogenic autoantibodies significantly declined in 4/5 patients. Neurological relapses occurred in three patients after a mean of 38 months of sustained stability, even if HM remitted. In such cases rituximab was administered but was associated with a shorter RFS time (1 year) compared to the previous BR scheme (3 years). In our case series, the combined BR regimen was a valid option in immune-mediated neuropathies associated with HM. Moreover, in some patients BR scheme allowed an earlier response and a long-lasting improvement than rituximab alone.

Outcomes after single-cycle rituximab monotherapy in patients with anti-MAG polyneuropathy: A bi-center experience with an average follow-up of 11 years.

Rituximab is efficacious in myelin-associated glycoprotein (MAG) polyneuropathy, but the question on timing of retreatments is open. We studied 21 anti-MAG polyneuropathy patients who responded to a first cycle of rituximab, were followed-up for an average of 11.2 years, and were retreated only when relapsing. Baseline serum B-cell-activating factor (BAFF) levels were measured. Clinical improvements lasted on average 6 years, and as many as 71% of the patients resulted long-lasting responders. Severity of disease and high serum BAFF levels (cut-off ≥860 pg/mL for relapse risk) at onset seemed to predict worse prognosis. Measurements of these variables could help deal with the issue of maintenance rituximab therapy in MAG polyneuropathy.

Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis.

In the human colon, vanilloid receptor TRPV1 is overexpressed both in afferent nerve terminals and in epithelial cells during inflammation. In the past years, pharmacological experiments using TRPV1 agonists and antagonists revealed that TRPV1 receptors may play proinflammatory and protective roles in the gastrointestinal tract. Here, we applied a genetic approach to define the role of TRPV1 and analyzed the effects of dinitrobenzene sulfonic acid (DNBS)-induced colitis in TRPV1-deficient (TRPV1-/-) mice. Intrarectal infusion of DNBS induced increased inflammation in TRPV1-/- mice compared to wild-type littermates (TRPV1+/+) as evaluated by macroscopic scoring and myeloperoxidase assays. This finding indicates that TRPV1 receptors are required for the protection within sensory pathways that regulate the response following the initiation of colonic inflammation. Electrophysiological recordings from circular smooth-muscle cells, performed 8 and 24 h after DNBS treatment, revealed strong spontaneous oscillatory action potentials in TRPV1-/- but not in TRPV1+/+ colons, indicating an early TRPV1-mediated control of inflammation-induced irritation of smooth-muscle activities. These unexpected results suggest that TRPV1 receptors mediate endogenous protection against experimentally induced colonic inflammation.

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice.

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.

Effects of sleep stage and age on short-term heart rate variability during sleep in healthy infants and children.

STUDY DESIGN: Power spectrum analysis of heart rate variability (HRV) is a noninvasive technique that provides a quantitative assessment of cardiovascular neural control. Using this technique, we studied the autonomic nervous system changes induced by sleep in 14 healthy subjects: 7 infants (mean age, 9.40 +/- 2.32 months) and 7 children (mean age, 8.93 +/- 0.65 years) during a standard all-night polysomnographic recording. Our primary aim was to assess the effect of sleep stage and age on short-term HRV during sleep in healthy infants and children. Power spectral density was estimated by autoregressive modeling over 250 consecutive R-R intervals. In this study, we mainly considered two spectral components: the high-frequency (HF) component (0.15 to 0.40 Hz), which reflects parasympathetic cardiovascular modulation; and the low-frequency (LF) component (0.04 to 0.15 Hz), generally considered due to both parasympathetic and sympathetic modulation. RESULTS: Heart rate was higher (p < 0.01 in all sleep stages) and total power lower (p < 0. 02) in infants than in children. HF power was higher in children than in infants (p < 0.05). In infants and children, the ratio between LF and HF powers changed with the various sleep stages (p < 0.02 in infants; p < 0.01 in children): it decreased during deep sleep and increased during rapid eye movement sleep. However, it was invariably lower in children than in infants. CONCLUSION: These findings show that the sleep stage and age both significantly influence short-term HRV during sleep in healthy infants and children. Hence, to provide unbiased results, HRV studies investigating the effects of age on autonomic nervous system activity should segment sleep into the five stages. In addition, despite a relatively small study sample, our data confirm greater parasympathetic control during sleep in children than in infants.

Increase in expression of the GABA(A) receptor alpha(4) subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists.

The effects of long-term exposure to, and subsequent withdrawal of, diazepam or imidazenil (full and partial agonists of the benzodiazepine receptor, respectively) on the abundance of GABA(A) receptor subunit mRNAs and peptides were investigated in rat cerebellar granule cells in culture. Exposure of cells to 10 microM diazepam for 5 days significantly reduced the amounts of alpha(1) and gamma(2) subunit mRNAs, and had no effect on the amount of alpha(4) mRNA. These effects were accompanied by a decrease in the levels of alpha(1) and gamma(2) protein and by a reduction in the efficacy of diazepam with regard to potentiation of GABA-evoked Cl- current. Similar long-term treatment with 10 microM imidazenil significantly reduced the abundance of only the gamma(2)S subunit mRNA and had no effect on GABA(A) receptor function. Withdrawal of diazepam or imidazenil induced a marked increase in the amount of alpha(4) mRNA; withdrawal of imidazenil also reduced the amounts of alpha(1) and gamma(2) mRNAs. In addition, withdrawal of diazepam or imidazenil was associated with a reduced ability of diazepam to potentiate GABA action. These data give new insights into the different molecular events related to GABA(A) receptor gene expression and function produced by chronic treatment and withdrawal of benzodiazepines with full or partial agonist properties.

Complexation of zolpidem with 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin: effect on aqueous solubility, dissolution rate, and ataxic activity in rat.

The effect of some chemically modified cyclodextrins [namely, 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin (HP-beta-CD, Me-beta-CD, and HP-gamma-CD, respectively)] on the aqueous solubility and dissolution rate of the hypnotic agent Zolpidem (ZP) was investigated. Solid complexes were prepared by freeze drying and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and dissolution rate of the drug were significantly improved by complexation with HP-beta-CD or Me-beta-CD. The structure of the inclusion complex ZP-HP-beta-CD in CH(3)COOD/D(2)O was investigated by (1)H and (13)C NMR spectroscopy, including NOE measurements. These measurements revealing a weak interaction between the tolyl moiety of the guest molecule and the HP-beta-CD cavity. The ataxic activity in rat was also investigated and it was found that ZP-HP-beta-CD and ZP-Me-beta-CD complexes showed almost 2-fold longer ataxic induction times than controls.

Stream nitrate variations explained by ground water head fluctuations in a pyrite-bearing aquifer.

In the context of agricultural nitrogen excesses in northwestern France, pyrite-bearing weathered schist aquifers represent important hydrological compartments due to their capacity to eliminate nitrate (NO3-). Under oxygen-free conditions, nitrate is reduced simultaneously with the oxidation of pyrite leading to the release of sulfate (SO4/2-). The aim of the present study is to identify the hydrological conditions under which the weathered schist ground water influences the stream water chemistry, leading to a decrease in NO3- concentration. We measured the ground water head on a small catchment over weathered schist, near the bank and under the streambed, and analyzed the chemical composition of the ground water as well as the stream water on both seasonal and storm-event timescales. Using SO4/2- as a tracer of the weathered schist ground water, we showed that ground water inflow caused a decrease of NO3- concentration in the stream during the autumn as well as during storm events in spring and summer. In summer, the NO3- concentration was controlled by the sources of the stream, and in winter by the shallow ground water inflow. The effect of the weathered schist ground water on the NO3- depletion remained relatively limited in time. This effect persisted into late autumn as long as the NO3(-) -rich shallow ground water did not feed the stream. The duration and intensity of the effect would be extended by decreasing the shallow ground water inflow, which depends on climate as well as the presence of landscape features such as hedges and buffer zones.

[Treatment of amyloidosis with dimethyl sulfoxide (DMSO)]. / Trattamento dell'amiloidosi con dimetilsulfossido (DMSO).

In this study we have investigated the role of oral dimethylsulfoxide (DMSO) therapy in 2 patients with primary amyloidosis (AL) and in 2 patients with secondary amyloidosis (AA) to long-standing rheumatoid arthritis. DMSO treatment produced no beneficial effects in the patients with idiopathic amyloidosis. Instead the patients with secondary amyloidosis experienced a subjective improvement, a decrease of inflammatory activity of the rheumatoid arthritis and an unequivocal improvement of renal function following 3-6 months of DMSO therapy. No serious side effects of DMSO were observed except for unpleasant breath odour. We conclude that a treatment with oral DMSO may prolong life of patients with secondary amyloidosis.

[Aberrant pancreas in gastric site]. / Il pancreas aberrante a sede gastrica

The conclusions contained in recent and past literature regarding the heterotopic pancreas are reviewed. A case of accessory pancreas located in the stomach, whose clinical, radiological and endoscopic aspects simulated a carcinomatous process, is reported. The case is studied anatomo-pathologically and important aspects, including surgical, noted.

[Hepatic distomiasis caused by Fasciola hepatica]. / La distomatosi epatica da fasciola hepatica

A case of bile duct obstruction due to Fasciola hepatica is presented. The evolution, aetiopathogenesis, symptomatology, diagnosis and therapy of this rare syndrome are then discribed.

[Cholecystosis]. / Le colecistosi

Cholecystosis conditions include those diseases of the gallbladder whose aetiopathogenesis is to be sought in a hyperplasia of the tissues making up the cholecystic wall (hyperplastic forms) and in an overload of this wall on the part of organic substances or minerals such as lipides or calcium salts (thesaurismosic forms). After discussing the classification, pathological anatomy, aetiopathogenesis, frequency, symptomatology, laboratory and radiological examinations, prognosis complications and treatment of these conditions, a personal series of 36 surgically treated cholecystoses is reported.

[Analysis of the results of 137 subclinical breast lesions excisions. Value of ultrasonography in the early diagnosis of breast cancer]. / Analyse des résultats de l'exérèse chirurgicale de 137 lésions mammaires infracliniques. Contribution de l'échographie dans le diagnostic précoce du cancer du sein.

OBJECTIVE: Ultrasonography is invaluable for evaluation of palpable masses and masses detected by mammography. Ultrasound has no proved role in breast screening. Between 1991 and 1994, we included ultrasonography routinely in our screening mammography prescription, not only for evaluation of mass detected by mammography but also in radiographically dense, non-radiolucent breast. One hundred and thirty-seven suspicious but non palpable breast lesions were detected. We analyzed the results of the surgical excision biopsies of these lesions and evaluated the contribution of ultrasonography combined with mammography to detect occult breast cancers. MATERIAL AND METHODS: From 1991 to 1994, our institution performed 8,489 individual screening mammographies. All women underwent physical examination before mammography. Women with abnormal clinical breast examination are not included in the study. Ultrasonography was routinely performed for characterization of a mass detected by mammography and also in normal breast with dense, non-radiolucent tissue. One hundred and thirty-seven suspected breast lesions were removed after immediate preoperative stereotaxic or US-guided needle localization. Screened women were aged 29-72 years (mean 51 years). 48% of all screened women were aged 50 years and older. RESULTS: The histopathologic findings were as follow: invasive ductal carcinoma (IDC) 40 cases (59%), invasive lobular carcinoma (ILC) 7 cases (10%), ductal carcinoma in situ 21 cases (31%). Infracllnic cancer was identified by mammography alone in 45% of cases, by mammography and sonography in 43.2% of cases, by sonography alone in 11.8% of cases. About 31% of infraclinic cancer occur prior to the age of 50 (age range: 29-72, mean: 54). Cancer less than 10 mm in diameter were found in 57.5% of lesions. Axillary dissection was performed in 46 cases of invasive cancer, with a incidence of axillary node metastases of 15%. CONCLUSION: The combination of mammography and ultrasonography is effective to detect a greater number of occult breast cancers and we recommend ultrasonography not only for evaluation of a mass detected by mammography but also in radiographically dense non-radiolucent breast lesions.

Cannabinoid type-1 receptors in the paraventricular nucleus of the hypothalamus inhibit stimulated food intake.

Cannabinoid receptor type 1 (CB1)-dependent signaling in the brain is known to modulate food intake. Recent evidence has actually shown that CB1 can both inhibit and stimulate food intake in fasting/refeeding conditions, depending on the specific neuronal circuits involved. However, the exact brain sites where this bimodal control is exerted and the underlying neurobiological mechanisms are not fully understood yet. Using pharmacological and electrophysiological approaches, we show that local CB1 blockade in the paraventricular nucleus of the hypothalamus (PVN) increases fasting-induced hyperphagia in rats. Furthermore, local CB1 blockade in the PVN also increases the orexigenic effect of the gut hormone ghrelin in animals fed ad libitum. At the electrophysiological level, CB1 blockade in slices containing the PVN potentiates the decrease of the activity of PVN neurons induced by long-term application of ghrelin. Hence, the PVN is (one of) the site(s) where signals associated with the body's energy status determine the direction of the effects of endocannabinoid signaling on food intake.