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.

The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium.

BACKGROUND: Poor oral hygiene has been proposed to contribute to head and neck cancer (HNC) risk, although causality and independency of some indicators are uncertain. This study investigates the relationship of five oral hygiene indicators with incident HNCs. METHODS: In a pooled analysis of 8925 HNC cases and 12 527 controls from 13 studies participating in the International Head and Neck Cancer Epidemiology Consortium, comparable data on good oral hygiene indicators were harmonized. These included: no denture wear, no gum disease (or bleeding), <5 missing teeth, tooth brushing at least daily, and visiting a dentist ≥once a year. Logistic regression was used to estimate the effects of each oral hygiene indicator and cumulative score on HNC risk, adjusting for tobacco smoking and alcohol consumption. RESULTS: Inverse associations with any HNC, in the hypothesized direction, were observed for <5 missing teeth [odds ratio (OR) = 0.78; 95% confidence interval (CI) 0.74, 0.82], annual dentist visit (OR = 0.82; 95% CI 0.78, 0.87), daily tooth brushing (OR = 0.83, 95% CI 0.79, 0.88), and no gum disease (OR = 0.94; 95% CI 0.89, 0.99), and no association was observed for wearing dentures. These associations were relatively consistent across specific cancer sites, especially for tooth brushing and dentist visits. The population attributable fraction for ≤ 2 out of 5 good oral hygiene indicators was 8.9% (95% CI 3.3%, 14%) for oral cavity cancer. CONCLUSION: Good oral hygiene, as characterized by few missing teeth, annual dentist visits, and daily tooth brushing, may modestly reduce the risk of HNC.

Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation.

Substance P (SP) is implicated in stress regulation and affective and anxiety-related behavior. Particularly high expression has been found in the main output region of the amygdala complex, the central amygdala (CE). Here we investigated the cellular mechanisms of SP in CE in vitro, taking advantage of glutamic acid decarboxylase-green fluorescent protein (GAD67-GFP) knockin mice that yield a reliable labeling of GABAergic neurons, which comprise 95% of the neuronal population in the lateral section of CE (CEl). In GFP-positive neurons within CEl, SP caused a membrane depolarization and increase in input resistance, associated with an increase in action potential firing frequency. Under voltage-clamp conditions, the SP-specific membrane current reversed at -101.5 ± 2.8 mV and displayed inwardly rectifying properties indicative of a membrane K(+) conductance. Moreover, SP responses were blocked by the neurokinin type 1 receptor (NK1R) antagonist L-822429 and mimicked by the NK1R agonist [Sar(9),Met(O2)(11)]-SP. Immunofluorescence staining confirmed localization of NK1R in GFP-positive neurons in CEl, predominantly in PKCδ-negative neurons (80%) and in few PKCδ-positive neurons (17%). Differences in SP responses were not observed between the major types of CEl neurons (late firing, regular spiking, low-threshold bursting). In addition, SP increased the frequency and amplitude of GABAergic synaptic events in CEl neurons depending on upstream spike activity. These data indicate a NK1R-mediated increase in excitability and GABAergic activity in CEl neurons, which seems to mostly involve the PKCδ-negative subpopulation. This influence can be assumed to increase reciprocal interactions between CElon and CEloff pathways, thereby boosting the medial CE (CEm) output pathway and contributing to the anxiogenic-like action of SP in the amygdala.

Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: rethinking the ARX phenotype in females.

Severe early-onset epilepsy is due to a number of known causes, although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, whereas heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. To investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy.

FLT3-targeted therapy restores GATA1 pathway function in NPM1/FLT3-ITD mutated acute myeloid leukaemia.

One-third of newly diagnosed adult acute myeloid leukaemia (AML) carry FLT3 mutations, which frequently occur together with nucleophosmin (NPM1) mutations and are associated with worse prognosis. FLT3 inhibitors are widely used in clinics with limitations due to drug resistance. AML cells carrying FLT3 mutations in both mouse models and patients present low expression of GATA1, a gene involved in haematopoietic changes preceding AML. Here, we show that FLT3 inhibition induces cellular responses and restores the GATA1 pathway and functions in NPM1/FLT3-ITD mutated AML, thus providing a new mechanism of action for this drug.

Equianalgesia, opioid switch and opioid association in different clinical settings: a narrative review.

Emergency or postoperative pain often represents an authentic challenge in patients who were already on opioid treatment for chronic pain. Thus, their management requires not only the physician's ability to treat acute pain, but also competence in switching the opioid that lost efficacy. Different aspects should be considered, such as opioids titration, switching, association and equianalgesia. The objective of this paper is to provide a narrative review, which has been elaborated and discussed among clinicians through an iterative process involving development and review of the draft during two web-based meetings and via email. This expert opinion aims to facilitate the correct opioid use through appropriate practices with a focus on pain treatment in emergency and postoperative pain. Equianalgesia tables were reviewed and integrated by clinicians and researchers with expertise in anesthesia, postoperative medicine, intensive care, emergency medicine pharmacology and addiction medicine. Special populations (liver/kidney failure, elder, pediatric, pregnancy/lactation) are discussed in detail along with other critical scenarios, such as: (i) rapid pain worsening in chronic pain (aggravating pain due to disease progression or tolerance development to analgesic therapy); (ii) acute pain on maintenance treatment; and (iii) pain management of complicated patients in emergency care. Extended and updated equianalgesia tables and conversion rates for 17 different opioid formulations (of 9 different molecules) are presented as follows. Opioids remain the class that best suits clinical needs of emergency and post-operative medicine. However, it should be stressed that equianalgesia can be affected by drug-to-drug interactions and pharmacological imprecision, in a complex field where clinical experience may be the main guiding principle.

Norovirus gastroenteritis and seizures: an atypical case with neuroradiological abnormalities.

We describe an 8-year-old boy admitted because of prolonged seizures during norovirus gastroenteritis without any signs of encephalopathy. Blood tests were normal and cerebrospinal fluid examination resulted negative for both bacteria and viruses. A reverse transcriptase polymerase chain reaction revealed norovirus RNA in a stool sample. A cerebral computed tomography turned out to be normal whereas subsequent cerebral magnetic resonance imaging showed transitory signal abnormalities consistent with vasogenic edema. The post-ictal electroencephalogram revealed normal background activity with sporadic left posterior delta waves. The child was discharged after 10 days with an unremarkable physical examination. A cerebral magnetic resonance imaging and an electroencephalogram after 1 month were both negative. We report a new case of benign infantile convulsions due to norovirus gastroenteritis with neuroradiological abnormalities to the pertinent literature in order to improve knowledge about this disorder and increase the possibility of clarifying its pathogenesis.

Percutaneous ultrasonography-guided core needle biopsy of gastrointestinal lesions: what's its actual role in clinical practice? A retrospective study for safety and effectiveness.

PURPOSE: Endoscopic biopsy is commonly performed to obtain a pathological diagnosis of gastrointestinal (GI) lesions. When the lesions are submucosal, subserosal, or exophytic, endoscopic biopsy is often unsuccessful, and endoscopic ultrasound (EUS)-guided biopsy is considered the procedure of choice in these cases. Nevertheless, in some patients both endoscopic and EUS-guided biopsy are not indicated, or yield inconclusive cyto-histological results. The aim of this study was to assess the efficacy and safety of percutaneous ultrasonography (US)-guided biopsy of GI wall lesions, and to define its actual role in clinical practice. MATERIALS AND METHODS: A retrospective study was conducted on 45 consecutive US-guided biopsies of GI lesions. All biopsies were performed in patients unsuitable for endoscopic or EUS-guided biopsy, or with lesions inaccessible to endoscopic techniques, or with inconclusive results from endoscopic or EUS-guided biopsy. Biopsies were performed with an 18 or 20-gauge Tru-cut needle under US guidance. Biopsy results were compared with the final diagnosis that was based on surgical pathological findings or clinical instrumental follow-up of at least 20 months. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), overall accuracy, and complication rate of the procedure were calculated. RESULTS: One biopsy specimen (2.2 %) was inadequate for cyto-histologic examination. In the remaining 44 cases, US-guided biopsy correctly identified 39 / 40 (97.5 %) malignant lesions, and 4 / 4 (100 %) benign lesions. One case resulted in a false negative (2.2 %). The sensitivity, specificity, PPV, NPV, and overall diagnostic accuracy were 97.5 %, 100 %, 100 %, 80 % and 97.7 %, respectively. Including also the inadequate specimen into the analysis, they were 95.1 %, 100 %, 100 %, 66.7 % and 95.6 %, respectively. No procedure-related complications were observed. In ten cases (22.2 %), US-guided biopsy results made it possible to avoid unnecessary surgical exploration. CONCLUSION: Percutaneous US-guided core biopsy of GI wall lesions is an accurate and safe technique that makes it possible in select cases to obtain a correct pathological diagnosis and prevent unnecessary surgical exploration. Although it has been replaced by EUS-guided biopsy as the procedure of choice to sample submucosal or subserosal GI lesions, US-guided biopsy can still play a useful role in the diagnostic workup of GI lesions when endoscopy or EUS is unsuccessful for various reasons or yields inconclusive cyto-histological results.

Familial Ohtahara syndrome due to a novel ARX gene mutation.

Recently, it has been reported that longer expansions of the polyalanine tract of the ARX gene could cause an early infantile encephalopathy with suppression burst pattern and that the length of this repeat region could be related to the severity of the electroclinical picture. We describe the history of two male individuals, born from monozygotic twin sisters, with Ohtahara syndrome (OS) that evolved into West syndrome phenotype and epileptic encephalopathy. In both children, we have found a previously unreported missense mutation in exon 5 of ARX gene (c.1604T>A) resulting in the substitution of a leucine with a glutamine in the aminoacid sequence. The two mothers and the maternal grandmother carry the same mutation which segregates with the disease phenotype in the family. This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations.

[Role of "gender" and "age" factors in the assessment of psychosocial risk and in prevention interventions of hospital personnel]. / Ruolo dei fattori "genere" ed "età" nella valutazione del rischio psicosociale e negli interventi di prevenzione del personale ospedaliero.

Gender, age and psychosocial risks. The paper reports research experience on nurses with special reference to "gender" and "age". Parameters such as "affectivity" and "work-family conflict" indicate the insufficiency of policies and actions to limit staff shortage and safeguard health till retirement age.

Severe epilepsy preceding by four months the onset of scleroderma en coup de sabre.

Juvenile localized scleroderma (JLS) includes several subtypes including plaque morphea, linear scleroderma and the en coup de sabre type which affects face and head. The latter variety may involve the eye and the brain with various appearance and clinical complications.We describe the case of a 6-year-old boy who presented partial complex seizures, with status epilepticus, four months before the appearance of sclerodermatous skin lesions on the face. This case report raises important questions on the pathogenesis of JLS and, particularly, on the issue whether it is a mere autoimmune condition or a neuro-cutaneous disease.

Transthoracic ultrasonography-guided core needle biopsy of pleural-based lung lesions: prospective randomized comparison between a Tru-cut-type needle and a modified Menghini-type needle.

PURPOSE: The diagnostic yield of the different types of cutting needles used to perform transthoracic biopsy is scarcely investigated. Aim of the study was to compare a Tru-cut-type (TCT) needle and a modified Menghini-type needle (MMT) in ultrasonography (US)-guided biopsy of pulmonary lesions. MATERIALS AND METHODS: 307 subjects (191 males and 116 females, mean age 58 years) with peripheral lung lesions selected to undergo US-guided biopsy were randomized to undergo biopsy by using an 18-gauge TCT or MMT needle. The specimens were imprinted on two to three slides for cytology and then put into a formalin solution for histology. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were calculated. Fisher's exact test was used to compare histology recovery rate (HRR), diagnostic accuracy, and diagnostic yield of the combination of cytology and histology in comparison with cytology alone and histology alone. RESULTS: 155 biopsies were performed using the MMT needle, 152 using the TCT needle. HRR was 112 / 155 (72.3 %) and 144 / 152 (94.7 %), respectively (p < 0.0001). Sensitivity, specificity, PPV, and NPV were 81.6 %, 100 %, 100 %, and 62 % for the former, respectively, and 93.6 %, 100 %, 100 %, and 86 % for the latter. A correct diagnosis was achieved in 133 / 155 biopsies (85.8 %) performed with the MMT needle, and in 145 / 152 biopsies (95.4 %) performed with the TCT needle (p = 0.0041). The combination of cytology and histology had a higher diagnostic yield than cytology alone (p < 0.001) and histology alone (p < 0.001). CONCLUSION: The TCT needle performs better than the MMT needle, and improves the diagnostic accuracy of US-guided transthoracic biopsy of superficial lung lesions.

[Prevention of psychosocial issues and drug addiction in workers employed in building great infrastructures: first outcomes of an experience in the Florence area]. / La prevenzione del disagio psicosociale lavorativo e delle dipendenze negli addetti alla realizzazione delle grandi opere infrastrutturali: primi risultati di uno esperienza in territorio fiorentino.

The research on stress, mobbing, and substance dependence in workers employed in the building of the great infrastructures is part of the project Euridice-Ten. The 75% of the workers employed took part in the research through an anonymous and structured questionnaire. The Clinica del Lavoro of the University of Milan elaborated the data. They point out a high risk of stress, a low level of control, a marked risk of mobbing, a high chronic fatigue in the most exhausting jobs, sleep disorders, problems in the social life as well as at home, in nourishment and at work. Many workers drink too much alcohol and the 9% of the workers know workers who use cocaine.

Linear IgA Bullous Dermatosis: A Series of 17 Cases. / Dermatosis ampollar IgA lineal: serie de 17 casos.

Linear IgA bullous dermatosis is an acquired subepidermal immunoglobulin-mediated vesiculobullous disease. In this retrospective, observational, descriptive study, we describe the clinical characteristics, treatments, and outcomes of 17 patients with linear IgA bullous dermatosis. Two children had been vaccinated 2 weeks before the onset of symptoms, 2 had had bronco-obstructive respiratory symptoms, and 1 had received intravenous antibiotic therapy. We also observed an association with autoimmune hepatitis in one patient and alopecia areata in another. One boy had VACTERL association. Diagnosis was confirmed by histopathology and direct immunofluorescence. Sixteen patients were treated with dapsone, which was combined with oral corticosteroids in 8 cases and topical corticosteroids in two. Of note in this series was the occurrence of relapses in the perioral area coinciding with infections and vaccination, and the association between linear IgA bullous dermatosis and autoimmune hepatitis and VACTERL association.

Reproducibility of rectal tumor volume delineation using diffusion-weighted MRI: Agreement on volumes between observers.

PURPOSE: To retrospectively evaluate the inter-observer agreement between a radiologist and a radiation oncologist and volume differences, in T2 and diffusion-weighted (DWI) MRI of gross tumor volume (GTV) delineation, in rectal cancer patients. MATERIALS AND METHODS: Two observers, a radiologist and a radiation oncologist, delineated GTVs of 50 patients on T2-weighted MRI (T2GTV) and echo planar DWI (DWIGTV). Observers agreement was assessed using DICE index, Bland-Altman analysis and intra-class correlation coefficient (ICC). Student's t-test was used for GTV comparison. RESULTS: Median T2GTV and DWIGTV were 17.09±14.12 cm3 (1.92-62.03) and 12.79±12.31 cm3 (1.23-62.25) for radiologist, and 16.82±13.66 cm3 (1.78-65.9) and 13.72±12.77 cm3 (1.29-69.75) for radiation oncologist. T2GTV were significantly larger compared to DWIGTV (P<0.001 and P<0.001, for both observers). Mean DICE index for T2GTV and DWIGTV were 0.80±0.07 and 0.77±0.06. The mean difference between the two observers were 0.26cm3 (95% CI: -5.36 to 5.88) and -1.13cm3 (95% CI: -5.70 to 3.44) for T2 and DWI volumes. The ICC for T2 volumes was 0.989 (95% CI: 0.981-0.994) (P<0.001) and 0.992 (95% CI: 0.986-0.996) (P<0.001) for DWI volumes. CONCLUSION: DWI resulted in smaller volumes delineation compared to T2-weighted MRI. Substantial and almost perfect agreements were reported for DWIGTV and T2GTV between radiologist and radiation oncologist. Due to the fact that DWI could be considered a simple technique for volume delineation for radiation oncologist, DWI could be used to improve quality in radiation planning for an accurate boost volume delineation when a dose escalation is investigated.

Clinical features of sarcomatoid renal cell carcinoma causing bilateral urinary tract obstruction.

We report on a 52-year-old female patient hospitalized because of uremia due to bilateral urinary tract obstruction caused by bilateral sarcomatoid renal cell carcinoma (SRCC). Abdominal computed tomography with contrast showed a large mass on the left side, infiltrating the left kidney, while the right kidney was described as enlarged. The latter was investigated with sonographic angiography using contrast and selective arteriography of the renal arteries, demonstrating a pseudonodular area at the inferior pole of the right kidney. The patient underwent bilateral nephrectomy and chronic hemodialysis treatment; unfortunately, after one month she died from cachexia. To the best of our knowledge this is the first case to be reported on bilateral SRCC causing bilateral urinary tract obstruction.

Main and interactive effects of shiftwork, age and work stress on health in an Italian sample of healthcare workers.

Among healthcare workers, shiftwork (mostly if nightwork is also included), ageing and work-related stress may be factors leading to impaired health. Such risk factors may also operate in interaction, resulting in an even increased harm for health. The present study aims at evaluating these relationships in a sample of 1842 hospital workers in Northern Italy. Subjects were mainly women, 33.1% were aged > or = 45 yr, and they were almost evenly distributed between dayworkers and rotating shiftworkers (nights included). Shiftwork was associated with poor sleep, while it was protective against gastrointestinal disorders, poor work ability and job dissatisfaction. Work stress was the risk factor with the highest relevance for poor health. Ageing was associated with lower physical health. Few significant interactions were observed. Shiftwork with nights and high work stress significantly interacted in increasing the risk for poor sleep. The "healthy worker effect" may have played a strong role in study findings.

A predictive model for the home outdoor exposure to nitrogen dioxide.

The aim of this study is to find and test a predictive model that could be suitable to estimate the outdoor NO(2) concentrations at individual level, by integrating ecological measurements recorded by local monitoring stations with individual information collected by a questionnaire. For this purpose, the data from the Italian centres of the European Community Respiratory Health Survey II (ECRHS II) has been used. Outdoor NO(2) concentrations were measured using NO(2) passive sampling tubes (PS-NO(2)), exposed outdoor for 14 days, between January 2001 and January 2003. Simultaneously, average NO(2) concentrations were collected from all the monitoring stations of the three centres (MS-NO(2)). Individual measurements carried out with passive samplers were compared with the corresponding NO(2) 2-week concentrations obtained as the average of all local (background and traffic) monitoring stations (MS-NO(2)). A multiple linear regression model was fitted to the data using the 2-week PS-NO(2) concentrations as the response variable and questionnaire information and MS-NO(2) concentrations as predictors. The model minimizing the root mean square error (RMSE), obtained from a ten-fold cross validation, was selected. The model with the best predictive ability included centre, season of the survey, MS-NO(2) concentrations, type and age of building, residential area and reported intensity of heavy-duty traffic and explained the 68.9% of the variance. The non-parametric correlation between PS-NO(2) and the concentrations estimated by the model is 0.81 (95% CI: 0.77-0.85). This study shows that over short periods (2 weeks) a good prediction of home outdoor exposure to NO(2) can be achieved by simply combining routinely collected ecological data with dwelling characteristics and self-reported intensity of heavy traffic. Further studies are needed to extend this prediction to long-term exposure.

Neuroimaging Changes in Menkes Disease, Part 2.

This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.