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1.  Assessment of Candida auris Response to Antifungal Drugs Using Time–Kill Assays and an Animal Model 
Open Forum Infectious Diseases  2017;4(Suppl 1):S73.
Candida auris is an emerging nosocomial pathogen that is resistant to Fluconazole and variably susceptible to other systemic drug classes. Treatment with echinocandins has been recommended based on MICs in the susceptible range, but supporting in vivo data is lacking.
We tested the MIC of C. auris strains (n = 12) to fluconazole, voriconazole, posaconazole. anidulafungin, amphotericin B and flucytosine. Representative C. auris strains from Israel and South Africa, and a reference C. albicans strain were analysed using time–kill curve assays. Fungicidal activity was defined as reduction of ≥3 log from baseline CFU/ml. Response to caspofungin treatment was assessed in BALB/c mice immunosuppressed with cyclophosphamide and inoculated with 7 × 107C. auris cells by tail vein injection. Mice were treated from day +1 to day +7 with caspofungin (IP) at doses of 1 or 5 mg/kg and compared with sham-treated controls. Survival was assessed daily. Kaplan-Meier survival analyses were performed and treatment arms were compared using the log-rank test.
Drug susceptibility results (MIC50 and MIC90) were: fluconazole, 64 and 128 mg/l; voriconazole, 0.5 and 24 mg/l; posaconazole, 0.5 and 27 mg/l; anidulafungin, 0.03 and 0.06 mg/l; amphotericin B, 2 and 8 mg/l; flucytosine, 0.3 and 1 mg/l. Time–kill curve analyses showed log reduction from baseline CFU concentration of −3.0 to −2.8 for fluconazole (MIC ×1), 5.6–6.1 for amphotericin B (MIC ×4) and −0.4 to −0.9 for caspofungin (MIC ×16), consistent with fungicidal activity of amphotericin B and weak fungistatic activity of caspofungin. In the mouse model, survival rate was similar with sham treatment (33%) and treatment with caspofungin 1 mg/kg/day (44%) and 5 mg/kg/day (22%), P = 0.7.
Despite generally low MIC, caspofungin has only mild fungistatic activity on C. auris and no effect on survival in a mouse infection model. Amphotericin B has fungicidal activity against C. auris.
All authors: No reported disclosures.
PMCID: PMC5631757
2.  Evaluating the Effectiveness of a Health Promotion Intervention Program Among Physiotherapy Undergraduate Students 
This study evaluated the effectiveness of a health promotion (HP) intervention program among physiotherapy undergraduate students in an academic institution by examining pre- and post-intervention health perceptions and behaviors compared to a control group (non-physiotherapy students).
Participants completed questionnaires on their health perceptions and behaviors at T1 (April 2009–May 2009) before the intervention program was initiated, and at T2 (April 2015–May 2015) after the intervention program was implemented for several years. At T1, 1,087 undergraduate students, including 124 physiotherapy students, participated. At T2, 810 undergraduate students, including 133 physiotherapy students participated.
Self-reported health-related perceptions and behaviors were compared in the study group (physiotherapy students) over time (T1 versus T2), and between the study group and the control group (non-physiotherapy students) pre-intervention (T1) and post-intervention (T2). Findings showed more positive perceptions and behaviors at T2 compared to T1 in the study group (51.0% at T2 versus 35.2% at T1; p<0.05). There was no significant difference at T2 compared to T1 in health perceptions reported by the control group (37.8% at T2 versus 32.8% at T1; non-significant difference).
Our findings demonstrated the effectiveness of the intervention program.
PMCID: PMC5525571  PMID: 28735335
Health Promotion; Motor Activity; Nutrition Assessment; Physical Therapists; Program Evaluation
3.  The association between multinucleated blastomeres and poor ovarian response under the Bologna criteria 
To investigate the occurrence of multinucleated blastomeres (MNB) in poor ovarian response (POR) women defined under the Bologna criteria.
This observational study was designed in a prospective controlled manner. Among 380 cases evaluated for eligibility, 102 women were found suitable and recruited; 51 with POR in accordance with the Bologna criteria defined as the study group and 51 with normal ovarian response defined as the control group.
Among the 51 women in each group, 8 and 2 did not achieve embryos in the study and control group, respectively (P < 0.05). The percentage of women that had at least one embryo with one MNB was significantly higher in the study as compared to the control group, corresponding to 49 and 29 %, respectively. The total number of embryos evaluated was 416; 167 in the study and 249 in the control groups. Among these embryos, the MNB rate was significantly higher in the study as compared to the control group, corresponding to 19 and 8 %, respectively.
Blastomere multinuclearity is significantly more common in women and embryos of POR cases, defined under the Bologna criteria. Future studies are warranted to substantiate our observation that has the potential to be clinically implemented in this sub-group of women undergoing assisted reproductive technologies (ART) treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s10815-016-0731-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4930787  PMID: 27169602
Assisted reproductive technologies; Bologna criteria; Multinucleated blastomere; Ovarian reserve; Poor ovarian response
4.  NK cell recognition of Candida glabrata through binding of NKp46 and NCR1 to fungal ligands Epa1, Epa6, and Epa7 
Cell host & microbe  2016;20(4):527-534.
Natural Killer (NK) cells form an important arm of the innate immune system and function to combat a wide range of invading pathogens, ranging from viruses to bacteria. However, the means by which NK cells accomplish recognition of pathogens with a limited repertoire of receptors remains largely unknown. In the current study, we describe the recognition of an emerging fungal pathogen, Candida glabrata, by the human NK cytotoxic receptor NKp46 and its mouse ortholog NCR1. Using NCR1 knockout mice, we observed that this receptor-mediated recognition was crucial for controlling C. glabrata infection in vitro and in vivo. Finally, we delineated the fungal ligands to be the C. glabrata adhesins Epa1, Epa6 and Epa7 and demonstrate that clearance of systemic C. glabrata infections in vivo depends on their recognition by NCR1. As NKp46 and NCR1 have been previously shown to bind viral adhesion receptors, we speculate that NKp46/NCR1 may be a novel type of pattern recognition receptor.
Graphical Abstract
PMCID: PMC5492882  PMID: 27736647
6.  Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel 
Emerging Infectious Diseases  2017;23(2):195-203.
Clinical features and experimentally deduced virulence indicate that C. auris has the greater lethal potential.
Candida auris and C. haemulonii are closely related, multidrug-resistant emerging fungal pathogens that are not readily distinguishable with phenotypic assays. We studied C. auris and C. haemulonii clinical isolates from 2 hospitals in central Israel. C. auris was isolated in 5 patients with nosocomial bloodstream infection, and C. haemulonii was found as a colonizer of leg wounds at a peripheral vascular disease clinic. Liberal use of topical miconazole and close contact among patients were implicated in C. haemulonii transmission. C. auris exhibited higher thermotolerance, virulence in a mouse infection model, and ATP-dependent drug efflux activity than C. haemulonii. Comparison of ribosomal DNA sequences found that C. auris strains from Israel were phylogenetically distinct from isolates from East Asia, South Africa and Kuwait, whereas C. haemulonii strains from different countries were closely interrelated. Our findings highlight the pathogenicity of C. auris and underscore the need to limit its spread.
PMCID: PMC5324804  PMID: 28098529
Candida auris; Candida haemulonii; virulence; bloodstream infection; antimicrobial resistance; Israel; fungi
7.  Empathy as a driver of prosocial behaviour: highly conserved neurobehavioural mechanisms across species 
Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well-being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions.
PMCID: PMC4685523  PMID: 26644596
empathy; evolution; biological mechanisms; caring; development; prosocial behaviour
8.  A prospective survey of Pseudomonas aeruginosa colonization and infection in the intensive care unit 
Pseudomonas aeruginosa (PA) surveillance may improve empiric antimicrobial therapy, since colonizing strains frequently cause infections. This colonization may be ‘endogenous’ or ‘exogenous’, and the source determines infection control measures. We prospectively investigated the sources of PA, the clinical impact of PA colonization upon admission and the dynamics of colonization at different body sites throughout the intensive care unit stay.
Intensive care patients were screened on admission and weekly from the pharynx, endotracheal aspirate, rectum and urine. Molecular typing was performed using Enterobacterial Repetitive Intergenic Consensus Polymerase Chain reaction (ERIC-PCR).
Between November 2014 and January 2015, 34 patients were included. Thirteen (38%) were colonized on admission, and were at a higher risk for PA-related clinical infection (Hazard Ratio = 14.6, p = 0.0002). Strains were often patient-specific, site-specific and site-persistent. Sixteen out of 17 (94%) clinical isolates were identical to strains found concurrently or previously on screening cultures from the same patient, and none were unique. Ventilator associated pneumonia-related strains were identical to endotracheal aspirates and pharynx screening (87–75% of cases). No clinical case was found among patients with repeated negative screening.
PA origin in this non-outbreak setting was mainly ‘endogenous’ and PA-strains were generally patient- and site-specific, especially in the gastrointestinal tract. While prediction of ventilator associated pneumonia-related PA-strain by screening was fair, the negative predictive value of screening was very high.
PMCID: PMC5225573  PMID: 28096975
Pseudomonas aeruginosa; Endogenous; Intensive Care unit; Surveillance; ERIC-PCR; Infection control
9.  Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities 
F1000Research  2016;5:2031.
Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility.
Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research.
Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback.
Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire.
Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.
PMCID: PMC5022703  PMID: 27781089
response rate; cohorts; symptoms; questionnaire; clinical trial
10.  Collecting clinical data in primary ciliary dyskinesia- challenges and opportunities 
F1000Research  2016;5:2031.
Rationale: Primary ciliary dyskinesia (PCD) is under diagnosed and underestimated. Most clinical research has used some form of questionnaires to capture data but none has been critically evaluated particularly with respect to its end-user feasibility and utility.
Objective: To critically appraise a clinical data collection questionnaire for PCD used in a large national PCD consortium in order to apply conclusions in future PCD research.
Methods: We describe the development, validation and revision process of a clinical questionnaire for PCD and its evaluation during a national clinical PCD study with respect to data collection and analysis, initial completion rates and user feedback.
Results: 14 centers participating in the consortium successfully completed the revised version of the questionnaire for 173 patients with various completion rates for various items. While content and internal consistency analysis demonstrated validity, there were methodological deficiencies impacting completion rates and end-user utility. These deficiencies were addressed resulting in a more valid questionnaire.
Conclusions: Our experience may be useful for future clinical research in PCD. Based on the feedback collected on the questionnaire through analysis of completion rates, judgmental analysis of the content, and feedback from experts and end users, we suggest a practicable framework for development of similar tools for various future PCD research.
PMCID: PMC5022703  PMID: 27781089
response rate; cohorts; symptoms; questionnaire; clinical trial
11.  Correction: Modulation of Host Angiogenesis as a Microbial Survival Strategy and Therapeutic Target 
PLoS Pathogens  2016;12(8):e1005838.
PMCID: PMC4988771  PMID: 27533051
12.  Thought-Controlled Nanoscale Robots in a Living Host 
PLoS ONE  2016;11(8):e0161227.
We report a new type of brain-machine interface enabling a human operator to control nanometer-size robots inside a living animal by brain activity. Recorded EEG patterns are recognized online by an algorithm, which in turn controls the state of an electromagnetic field. The field induces the local heating of billions of mechanically-actuating DNA origami robots tethered to metal nanoparticles, leading to their reversible activation and subsequent exposure of a bioactive payload. As a proof of principle we demonstrate activation of DNA robots to cause a cellular effect inside the insect Blaberus discoidalis, by a cognitively straining task. This technology enables the online switching of a bioactive molecule on and off in response to a subject’s cognitive state, with potential implications to therapeutic control in disorders such as schizophrenia, depression, and attention deficits, which are among the most challenging conditions to diagnose and treat.
PMCID: PMC4985062  PMID: 27525806
13.  Heteroresistance to Fluconazole Is a Continuously Distributed Phenotype among Candida glabrata Clinical Strains Associated with In Vivo Persistence 
mBio  2016;7(4):e00655-16.
Candida glabrata causes persistent infections in patients treated with fluconazole and often acquires resistance following exposure to the drug. Here we found that clinical strains of C. glabrata exhibit cell-to-cell variation in drug response (heteroresistance). We used population analysis profiling (PAP) to assess fluconazole heteroresistance (FLCHR) and to ask if it is a binary trait or a continuous phenotype. Thirty (57.6%) of 52 fluconazole-sensitive clinical C. glabrata isolates met accepted dichotomous criteria for FLCHR. However, quantitative grading of FLCHR by using the area under the PAP curve (AUC) revealed a continuous distribution across a wide range of values, suggesting that all isolates exhibit some degree of heteroresistance. The AUC correlated with rhodamine 6G efflux and was associated with upregulation of the CDR1 and PDH1 genes, encoding ATP-binding cassette (ABC) transmembrane transporters, implying that HetR populations exhibit higher levels of drug efflux. Highly FLCHR C. glabrata was recovered more frequently than nonheteroresistant C. glabrata from hematogenously infected immunocompetent mice following treatment with high-dose fluconazole (45.8% versus 15%, P = 0.029). Phylogenetic analysis revealed some phenotypic clustering but also variations in FLCHR within clonal groups, suggesting both genetic and epigenetic determinants of heteroresistance. Collectively, these results establish heteroresistance to fluconazole as a graded phenotype associated with ABC transporter upregulation and fluconazole efflux. Heteroresistance may explain the propensity of C. glabrata for persistent infection and the emergence of breakthrough resistance to fluconazole.
Heteroresistance refers to variability in the response to a drug within a clonal cell population. This phenomenon may have crucial importance for the way we look at antimicrobial resistance, as heteroresistant strains are not detected by standard laboratory susceptibility testing and may be associated with failure of antimicrobial therapy. We describe for the first time heteroresistance to fluconazole in C. glabrata, a finding that may explain the propensity of this pathogen to acquire resistance following exposure to fluconazole and to persist despite treatment. We found that, rather than being a binary all-or-none trait, heteroresistance was a continuously distributed phenotype associated with increased expression of genes that encode energy-dependent drug efflux transporters. Moreover, we show that heteroresistance is associated with failure of fluconazole to clear infection with C. glabrata. Together, these findings provide an empirical framework for determining and quantifying heteroresistance in C. glabrata.
PMCID: PMC4981708  PMID: 27486188
14.  Ploidy of spermatogenic cells of men with non-mosaic Klinefelter’s syndrome as measured by a computerized cell scanning system 
This study aims to characterize the origin of testicular post-meiotic cells in non-mosaic Klinefelter’s syndrome (KS).
The study included testicular tissue specimens from 11 non-mosaic KS patients, with (6 positive) and without (5 negative) spermatozoa presence. The obtained testicular cells were affixed and stained for morphology followed by fluorescence in situ hybridization (FISH) for centromeric probes X, Y, and 18. We used a computerized automated cell scanning system that enables simultaneous viewing of morphology and FISH in the same cell.
A total of 12,387 cells from the positive cases, 11,991 cells from the negative cases, and 1,711 cells from the controls were analyzed. The majority of spermatogonia were 47, XXY in both the positive and negative KS cases (88.9 ± 4.76 % and 90.6 ± 4.58 %) as were primary spermatocytes (76.8 ± 8.14 % and 79.6 ± 7.30 %). The respective rates of secondary spermatocytes and post-meiotic cells (round, elongating spermatids and sperm cells) were 1.1 ± 1.39 % in the positive cases, 2.9 ± 3.33 % in the negative cases, compared to 67.6 ± 6.22 % in the controls (P < 0.02). Pairing of both 18 and XY homologous chromosomes in 46,XY primary spermatocytes was 2.5 ± 2.31 % and 3.4 ± 2.39 %, respectively, compared to 19.8 ± 8.95 % in the control group (P < 0.02) and in 47,XXY primary spermatocytes in 2.4 ± 3.8 % in the positive group and 3.2 ± 2.26 % in the negative group.
This study presents data to indicate that the majority of primary spermatocytes in the testes of non-mosaic KS patients are 47,XXY and could possibly develop into post-meiotic cells.
PMCID: PMC4531865  PMID: 26081126
Ploidy; Testicular suspension; Klinefelter’s syndrome; Spermatogenic cells
15.  Anxiolytic Treatment Impairs Helping Behavior in Rats 
Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats’ subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat’s behavior on one session influenced his behavior on the next session. Results suggest that helping a trapped rat has a greater motivational value than does chocolate. In sum, this series of experiments clearly demonstrates the fundamental role of affect in motivating pro-social behavior in rodents and the need for a helper to resonate with the affect of a victim.
PMCID: PMC4896909  PMID: 27375528
emotional contagion; midazolam; empathy; helping; rodent; altruism
16.  Spatial and Spectral Characterization of Human Retinal Pigment Epithelium Fluorophore Families by Ex Vivo Hyperspectral Autofluorescence Imaging 
Discovery of candidate spectra for abundant fluorophore families in human retinal pigment epithelium (RPE) by ex vivo hyperspectral imaging.
Hyperspectral autofluorescence emission images were captured between 420 and 720 nm (10-nm intervals), at two excitation bands (436–460, 480–510 nm), from three locations (fovea, perifovea, near-periphery) in 20 normal RPE/Bruch's membrane (BrM) flatmounts. Mathematical factorization extracted a BrM spectrum (S0) and abundant lipofuscin/melanolipofuscin (LF/ML) spectra of RPE origin (S1, S2, S3) from each tissue.
Smooth spectra S1 to S3, with perinuclear localization consistent with LF/ML at all three retinal locations and both excitations in 14 eyes (84 datasets), were included in the analysis. The mean peak emissions of S0, S1, and S2 at λex 436 nm were, respectively, 495 ± 14, 535 ± 17, and 576 ± 20 nm. S3 was generally trimodal, with peaks at either 580, 620, or 650 nm (peak mode, 650 nm). At λex 480 nm, S0, S1, and S2 were red-shifted to 526 ± 9, 553 ± 10, and 588 ± 23 nm, and S3 was again trimodal (peak mode, 620 nm). S1 often split into two spectra, S1A and S1B. S3 strongly colocalized with melanin. There were no significant differences across age, sex, or retinal location.
There appear to be at least three families of abundant RPE fluorophores that are ubiquitous across age, retinal location, and sex in this sample of healthy eyes. Further molecular characterization by imaging mass spectrometry and localization via super-resolution microscopy should elucidate normal and abnormal RPE physiology involving fluorophores.
Translational Relevance
Our results help establish hyperspectral autofluorescence imaging of the human retinal pigment epithelium as a useful tool for investigating retinal health and disease.
PMCID: PMC4874453  PMID: 27226929
hyperspectral imaging; retinal pigment epithelium; lipofuscin; autofluorescence imaging; bisretinoids
17.  Host age modulates within-host parasite competition 
Biology Letters  2015;11(5):20150131.
In many host populations, one of the most striking differences among hosts is their age. While parasite prevalence differences in relation to host age are well known, little is known on how host age impacts ecological and evolutionary dynamics of diseases. Using two clones of the water flea Daphnia magna and two clones of its bacterial parasite Pasteuria ramosa, we examined how host age at exposure influences within-host parasite competition and virulence. We found that multiply-exposed hosts were more susceptible to infection and suffered higher mortality than singly-exposed hosts. Hosts oldest at exposure were least often infected and vice versa. Furthermore, we found that in young multiply-exposed hosts competition was weak, allowing coexistence and transmission of both parasite clones, whereas in older multiply-exposed hosts competitive exclusion was observed. Thus, age-dependent parasite exposure and host demography (age structure) could together play an important role in mediating parasite evolution. At the individual level, our results demonstrate a previously unnoticed interaction of the host's immune system with host age, suggesting that the specificity of immune function changes as hosts mature. Therefore, evolutionary models of parasite virulence might benefit from incorporating age-dependent epidemiological parameters.
PMCID: PMC4455738  PMID: 25994010
age-structured interactions; Daphnia–Pasteuria system; epidemiology; optimal virulence; stage-structured theory; trade-off hypothesis
18.  Modulation of Host Angiogenesis as a Microbial Survival Strategy and Therapeutic Target 
PLoS Pathogens  2016;12(4):e1005479.
PMCID: PMC4831739  PMID: 27078259
19.  Dural enhancement and thickening in acute mastoiditis 
The Neuroradiology Journal  2015;28(2):137-139.
Dural enhancement and thickening in imaging studies observed in acute mastoiditis patients is an uncommon phenomenon. It is infrequently seen in dural sinus thrombosis, and may be caused by infiltration of inflammatory cells and an increased number of thin-walled blood vessels. We present a three-year-old boy who presented with acute mastoiditis, complicated by subperiosteal abscess. Computerized tomography (CT) demonstrated subperiosteal abscess, and the child underwent mastoidectomy. Despite adequate treatment, symptoms worsened and neurological sequelae were suspected. CT and magnetic resonance imaging (MRI) studies demonstrated an atypical dural enhancement at the sigmoid perisinus and suboccipital abscess. The child underwent revision mastoidectomy and drainage of the abscess. Following the second procedure, resolution of symptoms was noted. Follow-up MRI did not demonstrate any dural pathologies.
PMCID: PMC4757156  PMID: 25963158
acute mastoiditis; MRI; complication; dural enhancement
20.  The Bologna criteria for poor ovarian response: a contemporary critical appraisal 
Postponement of child bearing and maternal age at first pregnancy are on the rise, contributing considerably to an increase in age-related infertility and the demand for assisted reproductive technologies (ART) treatment. This brings to the infertility clinics many women with low ovarian reserve and poor ovarian response (POR) to conventional stimulation. The Bologna criteria were released to standardize the definition of POR and pave the way for the formulation of evidence-based, efficient modalities of treatment for women undergoing IVF-ET. More than four years have passed since the introduction of these criteria and the debate is still ongoing whether a revision is due. Women with POR comprise several sub-groups with diverse baseline distinctiveness, a major issue that has fueled the discussion. Although antral follicle count (AFC) and anti-Müllerian hormone (AMH), are considered good predictors of ovarian reserve, their threshold values are still not universally standardized. Different definitions for sonographic AFC and diverse assays for AMH are held responsible for this delay in standardization. Adding established risk factors to the criteria will lead to more reliable and reproducible definition of a POR, especially in young women. The original criteria did not address the issue of oocyte quality, and the addition of risk factors may yield specific associations with quality vs. quantity. Patient’s age is the best available criterion, although limited, to predict live-birth and presumably oocyte quality. High scale studies to validate these criteria are still missing while recent evidence raises concern regarding over diagnosis.
PMCID: PMC4650906  PMID: 26577149
Poor ovarian response; Bologna criteria; Low ovarian reserve; Ovarian ageing; ART
Neuro-Oncology  2014;16(Suppl 5):v111-v112.
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) and relapsed high grade glioma (HGG) are incurable diseases with an event free survival of 6-8 months. Anti-Programmed Death 1 (anti-PD1) antibodies have recently emerged as a promising treatment modality in multiple cancer types. Clinical studies evaluating anti PD1 antibodies in the setting of primary brain tumors have not yet been reported. Pidilizumab (CureTech, Yavne, Israel) is an anti- PD1 humanized immunoglubulin G1 monoclonal antibody. This investigator-initiated clinical trial evaluates pidilizumab in malignant gliomas (NCT01952769). METHODS: Patients older than 3 years treated with not more than 2mg/M2 of dexamethasone per day are included. Patients with newly diagnosed DIPG are recruited for biweekly pidilizumab within the first month after completion of radiotherapy. Patients with HGG relapsed after standard treatment are recruited for biweekly pidilizumab as an add-on therapy to bevacizumab within 3 months of recurrence. The study was opened in February 2014. RESULTS: To date, 6 patients have been enrolled: three with newly diagnosed DIPG, two with HGG and one with relapsed DIPG (bevacizumab + pidilizumab). A total of 30 cycles of Pidilizumab (range 2- 14) have been administered. Treatment was well tolerated with transient fatigue as the main side effect. Administration of pidilizumab less than 10 days after bevacizumab resulted in a grade 3 blood pressure elevation in one patient. This did not recur when the interval between agents was increased. One patient withdrew because of parents' decision. One patient with HGG progressed and died within 2.5 months from enrollment. Two patients had a significant tumor shrinkage along with clinical improvement. Scheduled imaging evaluation is pending in the rest. CONCLUSION: The trial is ongoing. This report is confined to schedule and initial enrollment results.
PMCID: PMC4218260
22.  A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme 
Oncotarget  2015;6(30):28999-29015.
The blossom of immunotherapy in melanoma highlights the need to delineate mechanisms of immune resistance. Recently, we have demonstrated that the RNA editing protein, adenosine deaminase acting on RNA-1 (ADAR1) is down-regulated during metastatic transition of melanoma, which enhances melanoma cell proliferation and tumorigenicity. Here we investigate the role of ADAR1 in melanoma immune resistance.
Importantly, knockdown of ADAR1 in human melanoma cells induces resistance to tumor infiltrating lymphocytes in a cell contact-dependent mechanism. We show that ADAR1, in an editing-independent manner, regulates the biogenesis of miR-222 at the transcription level and thereby Intercellular Adhesion Molecule 1 (ICAM1) expression, which consequently affects melanoma immune resistance. ADAR1 thus has a novel, pivotal, role in cancer immune resistance. Corroborating with these results, the expression of miR-222 in melanoma tissue specimens was significantly higher in patients who had no clinical benefit from treatment with ipilimumab as compared to patients that responded clinically, suggesting that miR-222 could function as a biomarker for the prediction of response to ipilimumab.
These results provide not only novel insights on melanoma immune resistance, but also pave the way to the development of innovative personalized tools to enable optimal drug selection and treatment.
PMCID: PMC4745707  PMID: 26338962
melanoma; immune resistance; microRNA; ADAR1; ICAM1
23.  Sun Exposure and Protection Habits in Pediatric Patients with a History of Malignancy 
PLoS ONE  2015;10(9):e0137453.
Survivors of childhood cancer are at high risk for developing non-melanoma skin cancer and therefore are firmly advised to avoid or minimize sun exposure and adopt skin protection measures. We aimed to compare sun exposure and protection habits in a cohort of pediatric patients with a history of malignancy to those of healthy controls.
Case-control study of 143 pediatric patients with a history of malignancy (aged 11.2±4.6y, Male = 68, mean interval from diagnosis 4.4±3.8y) and 150 healthy controls (aged 10.4±4.8y, Male = 67). Sun exposure and protection habits were assessed using validated questionnaires.
Patients and controls reported similar sun exposure time during weekdays (94±82minutes/day vs. 81±65minutes/day; p = 0.83), while during weekends patients spent significantly less time outside compared to controls (103±85minutes/day vs. 124±87minutes/day; p = 0.02). Time elapsed from diagnosis positively correlated with time spent outside both during weekdays (r = 0.194, p = 0.02) and weekends (r = 0.217, p = 0.01), and there was a step-up in sun exposure starting three years after diagnosis. There was no significant difference regarding composite sun protection score between patients and controls. Age was positively correlated with number of sunburns per year and sun exposure for the purpose of tanning, and was negatively correlated with the use of sun protection measures.
Although childhood cancer survivors are firmly instructed to adopt sun protection habits, the adherence to these instructions is incomplete, and more attention should be paid to improve these habits throughout their lives. Since sunlight avoidance may results in vitamin D deficiency, dietary supplementation will likely be needed.
PMCID: PMC4562645  PMID: 26348212
24.  Ancient human genomes suggest three ancestral populations for present-day Europeans 
Lazaridis, Iosif | Patterson, Nick | Mittnik, Alissa | Renaud, Gabriel | Mallick, Swapan | Kirsanow, Karola | Sudmant, Peter H. | Schraiber, Joshua G. | Castellano, Sergi | Lipson, Mark | Berger, Bonnie | Economou, Christos | Bollongino, Ruth | Fu, Qiaomei | Bos, Kirsten I. | Nordenfelt, Susanne | Li, Heng | de Filippo, Cesare | Prüfer, Kay | Sawyer, Susanna | Posth, Cosimo | Haak, Wolfgang | Hallgren, Fredrik | Fornander, Elin | Rohland, Nadin | Delsate, Dominique | Francken, Michael | Guinet, Jean-Michel | Wahl, Joachim | Ayodo, George | Babiker, Hamza A. | Bailliet, Graciela | Balanovska, Elena | Balanovsky, Oleg | Barrantes, Ramiro | Bedoya, Gabriel | Ben-Ami, Haim | Bene, Judit | Berrada, Fouad | Bravi, Claudio M. | Brisighelli, Francesca | Busby, George B. J. | Cali, Francesco | Churnosov, Mikhail | Cole, David E. C. | Corach, Daniel | Damba, Larissa | van Driem, George | Dryomov, Stanislav | Dugoujon, Jean-Michel | Fedorova, Sardana A. | Romero, Irene Gallego | Gubina, Marina | Hammer, Michael | Henn, Brenna M. | Hervig, Tor | Hodoglugil, Ugur | Jha, Aashish R. | Karachanak-Yankova, Sena | Khusainova, Rita | Khusnutdinova, Elza | Kittles, Rick | Kivisild, Toomas | Klitz, William | Kučinskas, Vaidutis | Kushniarevich, Alena | Laredj, Leila | Litvinov, Sergey | Loukidis, Theologos | Mahley, Robert W. | Melegh, Béla | Metspalu, Ene | Molina, Julio | Mountain, Joanna | Näkkäläjärvi, Klemetti | Nesheva, Desislava | Nyambo, Thomas | Osipova, Ludmila | Parik, Jüri | Platonov, Fedor | Posukh, Olga | Romano, Valentino | Rothhammer, Francisco | Rudan, Igor | Ruizbakiev, Ruslan | Sahakyan, Hovhannes | Sajantila, Antti | Salas, Antonio | Starikovskaya, Elena B. | Tarekegn, Ayele | Toncheva, Draga | Turdikulova, Shahlo | Uktveryte, Ingrida | Utevska, Olga | Vasquez, René | Villena, Mercedes | Voevoda, Mikhail | Winkler, Cheryl | Yepiskoposyan, Levon | Zalloua, Pierre | Zemunik, Tatijana | Cooper, Alan | Capelli, Cristian | Thomas, Mark G. | Ruiz-Linares, Andres | Tishkoff, Sarah A. | Singh, Lalji | Thangaraj, Kumarasamy | Villems, Richard | Comas, David | Sukernik, Rem | Metspalu, Mait | Meyer, Matthias | Eichler, Evan E. | Burger, Joachim | Slatkin, Montgomery | Pääbo, Svante | Kelso, Janet | Reich, David | Krause, Johannes
Nature  2014;513(7518):409-413.
We sequenced the genomes of a ~7,000 year old farmer from Germany and eight ~8,000 year old hunter-gatherers from Luxembourg and Sweden. We analyzed these and other ancient genomes1–4 with 2,345 contemporary humans to show that most present Europeans derive from at least three highly differentiated populations: West European Hunter-Gatherers (WHG), who contributed ancestry to all Europeans but not to Near Easterners; Ancient North Eurasians (ANE) related to Upper Paleolithic Siberians3, who contributed to both Europeans and Near Easterners; and Early European Farmers (EEF), who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model these populations’ deep relationships and show that EEF had ~44% ancestry from a “Basal Eurasian” population that split prior to the diversification of other non-African lineages.
PMCID: PMC4170574  PMID: 25230663
25.  Reduced protein C Global assay level in infertile women prior to IVF-ET treatment 
In the last few years more robust evidence is emerging to point out at an increased rate of prematurity and low birth weight in singleton pregnancies following ART. Whether this increased rate is related to ART practice or to infertility per se, is still an open question. Our aim in this study was to explore this question by evaluating Protein C (ProC) Global assay in infertile women before ART treatment.
A cohort of 95 unselected and consecutive infertile women, eligible for ART, was prospectively recruited for the study. The control group included 77 matched healthy fertile women with a history of spontaneous conceptions. Pro C Global assay was evaluated in both groups. A full thrombophilic work-up was performed in the study group.
ProC Global assay level was found to be significantly lower in the study as compared to the control group, corresponding to 0.78 ± 0.16 and 0.88 ± 0.16, respectively (P < 0.01). As well, abnormal ProC Global assay level of ≤ 0.8 was significantly higher in the study as compared to control group corresponding to 53 % and 29 %, respectively. ProC Global assay level was significantly lower in women within the study group found to have APCR, factor V Leiden and high factor VIII level, any thrombophilia or combined thrombophilia when compared to women without these thrombophilic risk factors.
Reduced ProC Global assay level is encountered in infertile women prior to ART treatment. This finding may suggest a unique anticoagulation Protein C pathway in infertile as compared to fertile women. Further studies are encouraged to explore this finding.
PMCID: PMC3909128  PMID: 24189967
Assisted reproductive technologies; Perinatal risks; Protein C Global assay; Thrombophilia

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