apolipoproteine e4 allelic variant cognitive decline and psychosis in alzheimer disease a review of the literature and suggestions for upcoming studies

Apolipoprotein E (ApoE) e4 allele represents a well known vascular risk factor for developing Alzheimer disease (AD) and differences in ApoE genotypes may explain a part of the variability in AD phenotypes. In fact, ApoE e4 allele possession seems to be associated with a more precocious age of onset, greater episodic memory impairment, and psychotic symptoms. The first question we discuss regards the role of ApoE e4 on cognitive progression of AD. In fact, while a general agreement exists about the role played by ApoE e4 on the precocious onset of AD, cognitive decline has been differently associated with ApoE e4 allele possession in AD patients in a continuum of faster decline, no effect, and slower decline. An attemptable interpretation is that the biological processes leading to the onset of AD are different from those involved in determining its clinical course. The second question regards the possible relationship between the presence of the degenerative pathological hallmarks of the disease in specific cerebral areas and different cognitive or behavioural symptoms. In fact, there is evidence that degenerative pathology in hippocampal formation and frontal cortex reflects the progression of cognitive deficits in brain aging and AD and that hypometabolism in right frontal lobe and greater frontal neuropsychological deficits occur in AD patients with psychosis in comparison to those without. The third question regards, specifically, the relationship between ApoE e4 variant and behavioural symptoms. In fact, there is evidence supporting the link between being carriers of ApoE e4 allele and severity of delusions, mostly at the early stage of the illness. In an interpretative challenge, we suggest that the link between being carriers of ApoE e4 allele and suffering from delusions in AD may be explained by frontal lobe dysfunctions. Finally, we hypothesize that the most precocious onset of AD illness, described in carriers of ApoE e4 allelic variant, may also be related to the precocious onset of psychotic symptoms, which produces caregiver and patient distress and requires immediate assessment and treatment

Problematic mobile phone use in adolescence:a cross-sectional study

Aim: In recent years, mobile phone use has become increasingly common among Italian youth, while a growing scientific literature has been identifying the occurrence of a problematic mobile phone use which seems to share some features of other conditions often referred to as behavioural addictions. The study aimed to assess the prevalence of problematic mobile phone use in a population of Italian adolescents and its association with other behavioural addictions. Subjects and methods: The Mobile Addiction Test (MAT) was administered to 2,790 high school students from Barletta, an Italian town, together with the South Oaks Gambling Screen-Revised for Adolescents (SOGS-RA), the Compulsive Buying Scale (CBS), the Internet Addiction Test (IAT), the Exercise Addiction Inventory (EAI), the Work Addiction Risk Test (WART). Results: MAT scores fitted a Gaussian distribution model. Scores ≥ 17 was found as a cut-off value over which identifying problematic mobile phone users. Overall prevalence of problematic mobile phone use was 6.3%; this condition was associated with other behavioural addictions like compulsive buying. Conclusion: Problematic mobile phone use in adolescence should become a public health issue, and it could be a cause of health problems and social costs. © 2011 Springer-Verlag

Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer

Background: Complex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity. Methods: We generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis. Results: We demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes. Conclusion: We demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting

Oxcarbazepine improves mood in patients with epilepsy

Celem niniejszej analizy była prospektywna ocena, czy leczenie okskarbazepiną jest skorelowane z ilościową poprawą nastroju oraz zmniejszeniem objawów lękowych u dorosłych pacjentów z padaczką z napadami częściowymi. Objawy depresji oraz lęku oceniono za pomocą Skali Depresji Hamiltona (HDRS), Skali Dystymii Cornella (CDRS), Skali Depresji Becka (BDI) i Skali Lęku Hamiltona (HARS). Do badania włączono grupę kontrolną, składającą się z 40 pacjentów cierpiących z powodu padaczki i leczonych innymi lekami niż okskarbazepina, oraz grupę 40 pacjentów, których leczono okskarbazepiną. W badaniu z zastosowaniem skali CDRS wykazano istotną poprawę nastroju w przebiegu 3-miesięcznego okresu leczenia okskarbazepiną. Stwierdzono również poprawę wyników w skalach HDRS i BDI w grupie pacjentów leczonych okskarbazepiną, ale wynik ten nie był istotny statystycznie. Ponadto, w grupie 28 spośród 40 pacjentów leczonych okskarbazepiną, którzy prezentowali cechy dystymii według kryteriów skali CDRS na początku badania (wynik &#8805; 20 pkt.), stwierdzono poprawę nastroju zgodną z efektem przeciwdepresyjnym stosowanego leczenia (wynik < 20 pkt.). Mimo że prezentowane wyniki nie dostarczają ostatecznych dowodów, które uprawniałyby do stosowania okskarbazepiny jako leku przeciwdepresyjnego, znamienne zmniejszenie objawów dystymicznych w wyniku podawania okskarbazepiny w porównaniu z grupą kontrolną potwierdza hipotezę, że okskarbazepina poprawia nastrój.This study prospectively examined whether continued add-on treatment with oxcarbazepine (OXC) is associated with quantitative improvement in mood and anxiety symptoms in adult patients with partial epilepsy. Depressive symptoms and anxiety were assessed by clinical interview using the Hamilton Depression Rating Scale (HDRS), the Cornell Dysthymia Rating Scale (CDRS), the Beck Depression Inventory (BDI), and the Hamilton Anxiety Rating Scale (HARS). Forty controls (patients with epilepsy treated with antiepileptic drugs other than OXC) and 40 OXC-treated patients were enrolled and completed the study. In our study, a significant improvement in affect, as measured by the CDRS, was demonstrated during the course of OXC treatment for 3 months. HDRS and BDI scores also declined in the OXC-treated group, but these decreases did not reach statistical significance. In addition, 28 of 40 OXC-treated subjects who were dysthymic by CDRS criteria on study entry (score P20) demonstrated affective improvement consistent with a treatment-related antidepressant effect (score < 20). Although our results do not provide conclusive evidence supporting the specific use of OXC as an antidepressant, the significant decline in dysthymic symptoms in OXC-treated subjects compared with controls lends support to the hypothesis that OXC improves mood

High familial burden of cancer correlates with improved outcome from immunotherapy in patients with NSCLC independent of somatic DNA damage response gene status

Family history of cancer (FHC) is a hallmark of cancer risk and an independent predictor of outcome, albeit with uncertain biologic foundations. We previously showed that FHC-high patients experienced prolonged overall (OS) and progression-free survival (PFS) following PD-1/PD-L1 checkpoint inhibitors. To validate our findings in patients with NSCLC, we evaluated two multicenter cohorts of patients with metastatic NSCLC receiving either first-line pembrolizumab or chemotherapy. From each cohort, 607 patients were randomly case-control matched accounting for FHC, age, performance status, and disease burden. Compared to FHC-low/negative, FHC-high patients experienced longer OS (HR 0.67 [95% CI 0.46-0.95], p\u2009=\u20090.0281), PFS (HR 0.65 [95% CI 0.48-0.89]; p\u2009=\u20090.0074) and higher disease control rates (DCR, 86.4% vs 67.5%, p\u2009=\u20090.0096), within the pembrolizumab cohort. No significant associations were found between FHC and OS/PFS/DCR within the chemotherapy cohort. We explored the association between FHC and somatic DNA damage response (DDR) gene alterations as underlying mechanism to our findings in a parallel cohort of 118 NSCLC, 16.9% of whom were FHC-high. The prevalence of\u2009 65\u20091 somatic DDR gene mutation was 20% and 24.5% (p\u2009=\u20090.6684) in FHC-high vs. FHC-low/negative, with no differences in tumor mutational burden (6.0 vs. 7.6 Mut/Mb, p\u2009=\u20090.6018) and tumor cell PD-L1 expression. FHC-high status identifies NSCLC patients with improved outcomes from pembrolizumab but not chemotherapy, independent of somatic DDR gene status. Prospective studies evaluating FHC alongside germline genetic testing are warranted

Loss of FGFR4 promotes the malignant phenotype of PDAC

Transcriptomic analyses of pancreatic ductal adenocarcinoma (PDAC) have identified two major epithelial subtypes with distinct biology and clinical behaviours. Here, we aimed to clarify the role of FGFR1 and FGFR4 in the definition of aggressive PDAC phenotypes. We found that the expression of FGFR4 is exclusively detected in epithelial cells, significantly elevated in the classical PDAC subtype, and associates with better outcomes. In highly aggressive basal-like/squamous PDAC, reduced FGFR4 expression aligns with hypermethylation of the gene and lower levels of histone marks associated with active transcription in its regulatory regions. Conversely, FGFR1 has more promiscuous expression in both normal and malignant pancreatic tissues and is strongly associated with the EMT phenotype but not with the basal-like cell lineage. Regardless of the genetic background, the increased proliferation of FGFR4-depleted PDAC cells correlates with hyperactivation of the mTORC1 pathway both in vitro and in vivo. Downregulation of FGFR4 in classical cell lines invariably leads to the enrichment of basal-like/squamous gene programs and is associated with either partial or full switch of phenotype. In sum, we show that endogenous levels of FGFR4 limit the malignant phenotype of PDAC cells. Finally, we propose FGFR4 as a valuable marker for the stratification of PDAC patients

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Elaborazione delirante dell'esperienza di malattia in soggetto affetto da sclerosi multipla

Delusional elaboration of the disease experience in a patient with multiple sclerosi