Identifying the nature of episodic memory deficits in Major Depressive Disorder using a Real-World What-Where-When task.

ABSTRACTDeficits in episodic memory have been reported in various psychiatric conditions, including Major Depressive Disorder (MDD). Many widely used episodic memory tests do not have the ability to distinguish between impaired memory of separate components of a real-life event (e.g., what happened, where it happened and when), and impaired binding of such real-life features. To address this issue, a naturalistic, real-world What-Where-When memory task was employed to assess the nature of episodic memory impairments in MDD. A validation study established that the task is sensitive to age-related episodic memory changes, and that intentional encoding does not invalidate the task. The main study then compared the performance of patients with depression and control participants on the intentionally encoded WWW task. Patients with MDD presented an overall episodic memory impairment arising from deficits in object memory and the ability to bind objects to temporal context. Taken together, our study confirms the episodic memory impairment in MDD, by providing evidence of deficient object memory and reduced ability to bind temporal context to objects in patients. Our naturalistic WWW task presents a promising approach for thorough identification of the nature of episodic memory impairments, under a real-world environment, in various conditions, including MDD.

A Real-world What-Where-When Memory Test.

Episodic memory is a complex memory system which allows recall and mental re-experience of previous episodes from one's own life. Real-life episodic memories are about events in their spatiotemporal context and are typically visuospatial, rather than verbal. Yet often, tests of episodic memory use verbal material to be recalled (word lists, stories). The Real-World What-Where-When memory test requires participants to hide a total of 16 different objects in 16 different locations over two temporal occasions, 2 h apart. Another two hours later, they are then asked to recall which objects (What) they had hidden in which locations (Where) and on which of the two occasions (When). In addition to counting the number of correctly recalled complete what-where-when combinations, this task can also be used to test real-world spatial memory and object memory. This task is sensitive to normal cognitive aging, and correlates well with performance on other episodic memory tasks, while at the same time providing more ecological validity and being cheap and easy to run.

TiMEx: a waiting time model for mutually exclusive cancer alterations.

MOTIVATION: Despite recent technological advances in genomic sciences, our understanding of cancer progression and its driving genetic alterations remains incomplete. RESULTS: We introduce TiMEx, a generative probabilistic model for detecting patterns of various degrees of mutual exclusivity across genetic alterations, which can indicate pathways involved in cancer progression. TiMEx explicitly accounts for the temporal interplay between the waiting times to alterations and the observation time. In simulation studies, we show that our model outperforms previous methods for detecting mutual exclusivity. On large-scale biological datasets, TiMEx identifies gene groups with strong functional biological relevance, while also proposing new candidates for biological validation. TiMEx possesses several advantages over previous methods, including a novel generative probabilistic model of tumorigenesis, direct estimation of the probability of mutual exclusivity interaction, computational efficiency and high sensitivity in detecting gene groups involving low-frequency alterations. AVAILABILITY AND IMPLEMENTATION: TiMEx is available as a Bioconductor R package at www.bsse.ethz.ch/cbg/software/TiMEx CONTACT: niko.beerenwinkel@bsse.ethz.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Laquinimod (ABR-215062) for the treatment of relapsing multiple sclerosis.

Laquinimod (ABR-215062) is an oral immunomodulatory agent developed for the treatment of relapsing multiple sclerosis (MS). Laquinimod is a derivative of the drug roquinimex, but lacks the unacceptable side effect profile of this drug which was documented in previous MS trials. Preclinical studies in experimental models of MS, both of autoimmune neuroinflammation and of toxin induced demyelination show a multitude of immunomodulatory and anti-inflammatory effects, including some that are effective directly in the central nervous system. Phase I study results confirmed the safety and tolerability of laquinimod, and phase II and III studies provide a picture of a consistent albeit moderate effect on relapse rate and new lesion development on magnetic resonance imaging combined with a stronger effect on sustained progression and brain atrophy. These findings make laquinimod a potentially useful future treatment of MS.

Pseudo-Monocular Nystagmus Associated with Duane's Syndrome: Report of Two Cases.

PURPOSE: To present clinical findings and eye movement recordings of two children who had clinically apparent monocular nystagmus. METHODS: Full orthoptic and ophthalmological examination and eye movement recordings. RESULTS: An 8-year-old girl (patient 1) and a 13-month-old girl (patient 2) presented with right monocular nystagmus and right esotropia. A magnetic resonance imaging (MRI) scan of the brain obtained previously had been unremarkable for patient 2. Patient 1 had right amblyopia with visual acuity (VA) reduced to 20/400. Both patients had left abduction deficit and left palpebral fissure narrowing on adduction indicative of Duane's retraction syndrome. Patient 2 also had mild enophthalmos. Both patients had constant horizontal nystagmus in the right eye and very fine nystagmus in the left eye, which could only be detected on video and eye movement recordings. CONCLUSION: The existence of Duane's syndrome in both patients was masking the presence of nystagmus in the left eye, highlighting that detailed examination in this case can eliminate the need for neuroimaging. Interestingly, the dominant eye of both patients was on the side which was affected by Duane's syndrome, as there was less nystagmus in this eye.

Ectopic expression of Msx2 in mammalian myotubes recapitulates aspects of amphibian muscle dedifferentiation.

In contrast to urodele amphibians and teleost fish, mammals lack the regenerative responses to replace large body parts. Amphibian and fish regeneration uses dedifferentiation, i.e., reversal of differentiated state, as a means to produce progenitor cells to eventually replace damaged tissues. Therefore, induced activation of dedifferentiation responses in mammalian tissues holds an immense promise for regenerative medicine. Here we demonstrate that ectopic expression of Msx2 in cultured mouse myotubes recapitulates several aspects of amphibian muscle dedifferentiation. We found that MSX2, but not MSX1, leads to cellularization of myotubes and downregulates the expression of myotube markers, such as MHC, MRF4 and myogenin. RNA sequencing of myotubes ectopically expressing Msx2 showed downregulation of over 500 myotube-enriched transcripts and upregulation of over 300 myoblast-enriched transcripts. MSX2 selectively downregulated expression of Ptgs2 and Ptger4, two members of the prostaglandin pathway with important roles in myoblast fusion during muscle differentiation. Ectopic expression of Msx2, as well as Msx1, induced partial cell cycle re-entry of myotubes by upregulating CyclinD1 expression but failed to initiate S-phase. Finally, MSX2-induced dedifferentiation in mouse myotubes could be recapitulated by a pharmacological treatment with trichostatin A (TSA), bone morphogenetic protein 4 (BMP4) and fibroblast growth factor 1 (FGF1). Together, these observations indicate that MSX2 is a major driver of dedifferentiation in mammalian muscle cells.

ETIOLOGY AND RESISTANCE PROFILE OF ISOLATED STRAINS FROM SEVERE SYSTEMIC INFECTIONS IN PATIENTS WITH IMMUNODEPRESSION--EXPERIENCE OF THE IASI INFECTIOUS DISEASES HOSPITAL 2011-2014.

UNLABELLED: Microbial resistance is an increasingly serious threat to global public health and it is linked to patient's age, immune status, and also antibiotic overuse or misuse and repeated hospitalizations. The high incidence of infections caused by multidrug-resistant bacteria requires rethinking the first-line therapeutic schemes. AIM: Retrospective study of the etiologic and antibiotic resistance profile of the bacterial strains isolated from immunocompromised hosts diagnosed with severe systemic infections, aimed at gaining a better understanding of the potential infectious sources and optimizing the antibiotic therapy. MATERIAL AND METHODS: 178 cases of severe sepsis associated with immunosuppression (caused by diabetes, malignancies, liver cirrhosis, chronic alcohol abuse, kidney failure) were admitted to the "St. Parascheva" Infectious Diseases Hospital Iasi in the interval January 2011- December 2014. RESULTS: The mean age of the study patients was 61 years, most patients being female (53%) and living in urban areas (51%). The causal agents were: Escherichia coli (20.2%), Klebsiella pneumoniae (16.8%), Pseudomonas aeruginosa (14.6%), Methicillin-Sensitive Staphylococcus aureus (MSSA) (11.2%), Enterococcus spp. (10.1%), Methicillin-Resistant Staphylococcus aureus (MRSA) (8.9%), Proteus spp.(5%), Acinetobacter baumanii (5%), Streptococcus pyogenes (1.6%), Staphylococcus epidermidis (1.1%) and Citrobacter (0.5%). As to the resistance profile the following were found: 100% susceptibility of MRSA and Enterococcus species to vancomycin, as well as for the Enterococcus species; 27% of E. coli strains were resistant to beta-lactams and 20% of Klebsiella pneumoniae to carbapenems. Antibiotic therapy associated two or three drugs with an immediate result and a favorable outcome in 84.2% of the cases. CONCLUSIONS: The etiological agents implicated in the occurrence of severe sepsis in patients with acquired immunosuppression were Gram-positive bacteria (GPB) as well as Gram-negative bacteria (GNB) with moderate resistance to usual antibiotics. The infections caused by GNB were predominant in immunocompromised patients, but also in those with associated urinary and respiratory tract infections and chronic indwelling urinary catheters. In our severe sepsis patients Gram positive bacteria caused mainly skin and joint infections.

Hepatorenal dysfunction in sepsis: epidemiological, clinical and laboratory aspects.

UNLABELLED: The major impact of sepsis-induced multiple organ dysfunction on healthcare system in the European Union was estimated at 90.4 cases per 100000 inhabitants, compared to 58 per 100000 for breast cancer. The association of organ dysfunctions in terms of both the number of dysfunctions and the degree of organ dysfunction is the most powerful predictor of death in sepsis. AIM: To find medical and statistical correlations in hepatorenal dysfunction in sepsis patients. MATERIAL AND METHODS: This retrospective study included 117 patients diagnosed with sepsis at the Iasi Infectious Diseases Hospital, patients who presented liver/renal and other organ dysfunctions. The clinical, etiological, and laboratory data, and APACHE II prognostic scores were analyzed. The data were processed using SPSS version 16.0. RESULTS: The etiological agents were Gram positive as well as Gram negative bacteria, and 40% of sepsis patients with hepatic/kidney dysfunction presented hepatorenal syndrome. CONCLUSIONS: Over one-third of patients with sepsis-related hepatorenal dysfunction had a creatinine clearance of less than 30 ml/min, and we found statistical correlations between serum creatinine and APACHE II score. There were no statistically significant differences between the survival curves of patients with hepatorenal syndrome and those with sepsis-related hepatorenal dysfunction.

Transcriptomic responses of cancerous and noncancerous human colon cells to sulforaphane and selenium.

Diets enriched with bioactive food components trigger molecular changes in cells that may contribute to either health-promoting or adverse effects. Recent technological advances in high-throughput data generation allow for observing systems-wide molecular responses to cellular perturbations with nontoxic and dietary-relevant doses while considering the intrinsic differences between cancerous and noncancerous cells. In this chemical profile, we compared molecular responses of the colon cancer cell line HT29 and a noncancerous colon epithelial cell line (HCEC) to two widely encountered food components, sulforaphane and selenium. We conducted this comparison by generating new transcriptome data by microarray gene-expression profiling, analyzing them statistically on the single gene, network, and functional pathway levels, and integrating them with protein expression data. Sulforaphane and selenium, at doses that did not inhibit the growth of the tested cells, induced or repressed the transcription of a limited number of genes in a manner distinctly dependent on the chemical and the cell type. The genes that most strongly responded in cancer cells were observed after treatment with sulforaphane and were members of the aldo-keto reductase (AKR) superfamily. These genes were in high agreement in terms of fold change with their corresponding proteins (correlation coefficient r(2) = 0.98, p = 0.01). Conversely, selenium had little influence on the cancer cells. In contrast, in noncancerous cells, selenium induced numerous genes involved in apoptotic, angiogenic, or tumor proliferation pathways, whereas the influence of sulforaphane was very limited. These findings contribute to defining the significance of cell type in interpreting human cellular transcriptome-level responses to exposures to natural components of the diet.

Fetal and neonatal alloimmune thrombocytopenia.

UNLABELLED: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the commonest cause of severe neonatal thrombocytopenia. FNAIT is usually suspected in neonates with bleeding or severe, unexplained, and/or isolated postnatal thrombocytopenia. Affected fetuses should be managed in referral centers with experience in the ante-natal management of FNAIT. Close collaboration is required between specialists in fetal medicine, obstetrics, hematology/transfusion medicine, and pediatrics. The mother and her partner should be provided with detailed information about FNAIT and its potential clinical consequences, and the benefits and risks of different approaches to ante-natal management. There has been huge progress in the ante-natal management of FNAIT over the last 20 years. However, the ideal effective treatment without significant side effects to the mother or fetus has yet to be determined. KEY ISSUES: Fetal and neonatal alloimmune thrombocytopenia is a condition that is underdiagnosed.Immunization seldom occurs in the first pregnancy.Immunization takes place in association with delivery in most cases.Anti-HPA-1a level is a predictor for the severity of thrombocytopenia.