Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences.We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up.Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide. She had a medical history of lobular carcinoma of the left breast treated with mastectomy and chemotherapy in 2012, Hashimoto thyroiditis, arterial hypertension. There was no prior neurological disorder and physical examination was unremarkable. Coagulation tests showed reduced prothrombin time ratio (59%) and normal activated partial thromboplastin time, a slightly reduced fibrinogen  and increased D-dimer (8634 μg/L). Bone marrow evaluation was consistent with acute promyelocytic leukemia (APL) according to French-American-British (FAB) classification system. The patient was started on all-trans retinoic acid (45 mg/m2) according to protocol APL0406Although polyneuropathy is common following arsenic trioxide therapy of subjects with acute promyelocytic leukemia (APL), symptoms are generally mild and they disappear after completion of arsenic treatment. In November 2014, a 72-year old Caucasian woman was admitted to this Unit with fever and pancytopenia , neurological symptoms were attributed to sodium-related hyperosmolarity.Over the following days an impaired level of consciousness and lethargy was noticed. Progressive and appropriate normalization of natriemia did not improve neurological dysfunction.Additional diagnostic procedures were performed. A CT scan of the brain did not reveal abnormalities related to the acute clinical picture, showing only age-related mild cerebral and cerebellar atrophy. Cerebrospinal fluid showed only mild protein elevation.Plasma levels of vitamin B1 were low  and supplementation was started. Over the following 5 days the patient showed a slow but progressive full recovery of cognitive functions.Unexpectedly, at normalization of cognitive function, a pattern of symmetric peripheral neuropathy involving upper and lower limbs became clinically evident. Physical examination showed that left and right hands were severely weak, particularly the abductor pollicis brevis, with mild strength reduction in the proximal arms. Deep-tendon reflexes were absent. There was bilateral foot drop, and the patient was unable to walk. Strength in the ankle dorsiflexors, extensor hallucis longus, extensor digitorum brevis, and toe flexors was severely compromised. There was no muscle atrophy or fasciculation, and the remainder of the neurologic examination was normal. Electromyography (EMG) showed a severe sensory-motor axonal neuropathy of the upper and lower extremities with a greater reduction of sensory action potential.Meanwhile on day 28 arsenic trioxide had been stopped according to the therapy protocol. Bone marrow evaluation showed molecular remission. At that time the patient was bedridden because of a severe neurological impairment, so we chose not to administer consolidation therapy as it would have been required according to standard protocol.Over the following on 6 months from arsenic trioxide discontinuation, the patient regained full proximal muscle strength but with almost complete persistence of marked distal weakness of the hands,ly finger and wrist extensors, weakness of foot dorsiflexors bilaterally and the inability to maintain an upright position. Neurological examination and EMG were substantially unchanged at the 12-month follow-up evaluation.We believe that occult thiamine deficiency exacerbated arsenic trioxide neurotoxicity causing an unexpected and irreversible distal axonal symmetric neuropathy. This is the first report of acute and irreversible axonal neuropathy in a patient treated with arsenic trioxide with a background of thiamine deficiency. Peripheral neuropathy has long since been associated with the use of arsenic. Several clinical studies have been published on ATO treatment of patients with APL .2–12 AltSevere and irreversible arsenic neurotoxicity in the setting of thiamine deficiency can be explained by their common metabolic target. In fact, thiamine deficiency and arsenic exposure severely impair pyruvate dehydrogenase (PDH) activity, an enzyme responsible for converting glucose to energy in high yield. As neural tissues are highly dependent on carbohydrates for energy production and cellular metabolism, it is tempting to speculate a synergic detrimental neuropathic effect leading to the severe toxicity observed in our patient. Of interest, we found electrophysiological findings consistent with acute axonal dysfunction without pattern of demyelination. This type of damage is the classic electrophysiological and histopathological finding in beriberi neuropathy whereas arsenic axonal toxicity characteristically coexists with segmental demyelination.17In conclusion, occult thiamine deficiency may contribute to arsenic toxicity and the combination may cause irreversible axonal neuropathy which must be considered when monitoring APL patients on arsenic trioxide therapy. Prophylactic administration of thiamine may be considered in this setting.


Mental disorders affect up to 40 % of all individuals living in Europe at least once a life time. Serious mental disorders with chronic or relapsing course like major depression bipolar disorder and schizophrenia are disabling and often disintegrating disorders. The early identification of subjects being at risk for serious mental disorders holds the promise of early intervention and better long-term outcomes. However, still reliable early indicators are largely missing to date. Like in dementia research major research initiatives need to be developed to address those urgent issues.New MRI imaging technique, genotyping, gene methylation analyses, metabolom analyses, validated questionnaires for the assessment of psychosocial risk factors.Advanced statistical modeling of brain imaging data, support vector machine approaches, systems integration of OMICS data; data mining approaches for risk marker identification.The identification of peripheral risk indicators of severe mental diseases is probably limited to rare but highly penetrative genetic variants. Possibly gene-methylation patterns that emerge in the light of abuse and traumatization be constitute another source of valuable information. The non-invasive MRI imaging technologies might be very promising but still time consuming and expensive. Especially functional MRI studies are only feasible in specialist centers. The most promising approach seems to create a set of specific markers throughout the different levels of information to integrate biological, psychosocial and structural information on each subject.


Spontaneous cortical activity can show very complex collective emerging features, with, in some cases, the alternation of "down states" of network quiescence and "up states" of generalized spiking and neuronal depolarization . Results


THHOBO data loggers and rainfall was recorded daily using GENERALR wireless rain gauges. Thin plate spline (TPS) was used to interpolate, with the degree of data smoothing determined by minimizing the generalized cross validation. The dataset provide information on the status of the current climatic conditions along the two mountainous altitudinal gradients in Kenya and Tanzania. The dataset will, thus, enhance future research.Climate change is a global concern, requiring local scale spatially continuous dataset and modeling of meteorological variables. This dataset article provided the interpolated temperature, rainfall and relative humidity dataset at local scale along Taita Hills and Mount Kilimanjaro altitudinal gradients in Kenya and Tanzania, respectively. The temperature and relative humidity were recorded hourly using automatic onset  Specifications TableValue of the data•The data provide information on the status of the climatic conditions along the two mountain altitudinal gradients in Kenya and Tanzania, and includes data accessible for reuse.•The data are important to farming communities, agricultural extension agents, government institutions, international and local non-governmental organizations engaged in agricultural interventions, including useful data to researchers, students and academics.•The data can be used for mapping and spatial modeling in a geographical information system (GIS).•The data is valuable for improvements computational facilities, insufficient climate data and reliable downscaling at a local scale.•The data are important in making confidentially informed decisions, giving scientists accurate spatially continuous data cross a region for making justified interpolation.12R wireless rain gauges were installed at station across study sites to keep track of daily temperatures, relative humidity and rainfall, respectively x–y coordinates position and altitudes were recorded using a Global Positioning System (GPS) (German eTrex Vista(R)). The thin plate spline (TPS) algorithm 2); (ii) the Root Mean Square Error (RMSE); and (iii) the Relative Root Mean Square Error (RMSEr).The details of the sites have been described in our previous study


Diverse monogenic autoinflammatory diseases share responsiveness to interleukin (IL)-1 blockade. This study explored the utility of anakinra (an IL-1 receptor antagonist) as a treatment option for clinically heterogeneous systemic inflammatory disease with autoinflammatory presentations where a genetic cause was not defined.A total of ten adult cases with ongoing inflammatory episodes, where alternative diagnoses, including malignancy and infection, were evaluated. Genetic screening was also performed to exclude known genetic causes of autoinflammatory disorders (e.g. cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), etc.)All patients had presentations that were atypical of recognised autoinflammatory disorders and all were negative on genetic screening. Eight of ten cases showed rapid responsiveness to anakinra with the ability to subsequently taper alternative immunosuppression. Good responses to anakinra were maintained with inadvertent drug discontinuation being linked to disease flares.The spectrum of poorly defined clinical and genetic autoinflammatory disorders that show responsiveness to anakinra is considerable. In fact, responsiveness to anakinra appears to be useful in diagnosis given the characteristically rapid onset of efficacy and symptomatic improvement.


Aging may lead to pathologies due to the physiologic decline or aberrancy in the functions of adult stem cells, whose intrinsic capacity for self-renewal helps maintain tissue homeostasis. The majority of cancers arise from replication-induced somatic mutations in adult stem cells , which pAPC or CTNNB1 mutations, which are found in >90% of early colon adenomas [mut) in late colon adenomas drive their malignant transformation to cancer by further promoting WNT activation through β-catenin nuclear localization [per se, even when targeted to murine colon stem cells to constitutively activate their intestinal stem cell program, was capable of initiating colon adenomas but not invasive colon cancers [Hitherto, the initiation of colon cancer has been attributed mainly to the aberrant activation of WNT signaling as a result of adenomas . Indeed,lization . However cancers . Nearly  cancers . Thus thmut further increases this tumorigenic and dedifferentiation program [mut to dedifferentiate APC mutated colon adenoma cells depends on their moderate plasticity, since KRASmut by itself in the cellular context of differentiated epithelial cells cannot induce the embryonic stem cell-like program [in vivo plasticity model in which the achievement of high plasticity, as exemplify by KRASmut mediated induction of the embryonic stem cell-like program in colon adenomas, optimizes colon cancer initiation. Currently, there are two conflicting theories for the colon cancer cells of origin. The top-down theory requires that differentiated crypt top colon cells undergo dedifferentiation to become the colon cancer cells of origin. The bottom-up theory suggests that crypt base WNT activated colon stem cells, which give rise to colon adenomas, are the colon cancer cells of origin [in vivo plasticity model helps explain the paradoxical findings that lend support to both the top-down and bottom-up theories on the colon cancer cells of origin.We have found that embryonic stem cell-like program activation is a major mechanistic driver of colon cancer initiation, and the presence of KRAS program . The abi program , 7. We hf origin . Howevermut tumors.Intriguingly, embryonic stem cells arise at the beginning of human ontogeny and cancer cells arise dramatically toward the end. Thus cancer cells have come nearly full circle in reactivating the embryonic stem cell-like program, which imparts greater phenotypic plasticity to thrive with environmental variations. Cancers may be the unfortunate failed manifestations of nature's quest for the fountain of youth. Nevertheless, the inhibition of the embryonic stem cell-like program offers novel therapeutic strategies to prevent cancer and inhibit KRAS


A striking property of the mutualism between figs and their pollinating wasps is that wasps consistently oviposit in the inner flowers of the fig syconium, which develop into galls that house developing larvae. Wasps typically do not use the outer ring of flowers, which develop into seeds. To better understand differences between gall and seed flowers, we used a metatranscriptomic approach to analyze eukaryotic gene expression within fig flowers at the time of oviposition choice and early gall development. Consistent with the unbeatable seed hypothesis, we found significant differences in gene expression between gall- and seed flowers in receptive syconia prior to oviposition. In particular, transcripts assigned to flavonoids and carbohydrate metabolism were significantly up-regulated in gall flowers relative to seed flowers. In response to oviposition, gall flowers significantly up-regulated the expression of chalcone synthase, which previously has been connected to gall formation in other plants. We propose several genes encoding proteins with signal peptides or associations with venom of other Hymenoptera as candidate genes for gall initiation or growth. This study simultaneously evaluates the gene expression profile of both mutualistic partners in a plant-insect mutualism and provides insight into a possible stability mechanism in the ancient fig-fig wasp association. Mutualisms are ubiquitous in nature and often enhance the nutrition, protection, and/or reproduction of participating partners see , 2). Yet. Yet2]).Ficus spp.) and fig wasps  arose >80 million years ago ).Use of only a subset of available flowers by foundresses cannot be explained by physical limitations in ovipositor length or egg number , 23, 24.Based on observations that foundresses are selective in choosing flowers for oviposition, West and Herre  proposedFicus obtusifolia, a monoecious fig that grows natively in lowland forests in Panama. Specifically we compared metatranscriptomes of gall and seed flowers before and after fig wasps entered syconia to determine (1) biochemical and metabolic differences between these two flower types that may influence oviposition by foundress wasps, and (2) gene expression in floral tissue at gall initiation ). The high level of expression of these genes suggests that fig wasps were undergoing embryogenesis when gall flowers were collected.The hymenopteran transcript with the highest level of expression was assigned to the gene properly . AdditioA maternal secretion, which is deposited in every flower that receives an egg, has been associated with the initiation of gall growth in fig flowers , 67, 68.th highest expressing in all Hymenoptera transcripts) was assigned to icarapin, which has an active role in honeybee venom [Nasonia vitripennis, the only well-studied venom among wasps in the superfamily of Chalcidoidea, eight genes coding for proteins harboring signal peptides also shared homology with genes coding for venom proteins. Three are hypothetical proteins and the remaining five match genes predicted as serine protease, lysosomal acid phosphatase, chymotrypsin, lipase, and metalloproteinase (Table G in Eulophus pennicornis [Only 196 (2.8%) of the Hymenopteran transcripts observed here contain a signal peptide Click here for additional data file.S1 FileNumber of transcripts assigned to taxonomic groups for each sample (Table A). Overrepresented GO terms of up-regulated genes in receptive gall flowers compared to receptive seed flowers (Table B). Transcripts assigned to overrepresented GO terms associated with chalcone synthase in receptive and pollinated gall flowers (Table C). Transcripts uniquely expressed in receptive gall flowers (Table D). Transcripts assigned to overrepresented GO terms associated with carbohydrate metabolism in receptive gall flowers (Table E). Overrepresented GO terms of up-regulated genes in pollinated gall flowers compared to receptive gall flowers and pollinated seed flowers (Table F). Transcripts with assignment to Hymenoptera (Table G).(XLSX)Click here for additional data file.


Women seeking to become pregnant and pregnant women are currently advised to consume high amounts of folic acid and other methyl donors to prevent neural tube defects in their offspring. These diets can alter methylation patterns of several biomolecules, including nucleic acids, and histone proteins. Limited animal model data suggests that developmental exposure to these maternal methyl supplemented (MS) diets leads to beneficial epimutations. However, other rodent and humans studies have yielded opposing findings with such diets leading to promiscuous epimutations that are likely associated with negative health outcomes. Conflict exists to whether these maternal diets are preventative or exacerbate the risk for Autism Spectrum Disorders (ASD) in children. This review will discuss the findings to date on the potential beneficial and aversive effects of maternal MS diets. We will also consider how other factors might influence the effects of MS diets. Current data suggest that there is cause for concern as maternal MS diets may lead to epimutations that underpin various diseases, including neurobehavioral disorders. Further studies are needed to explore the comprehensive effects maternal MS diets have on the offspring epigenome and subsequent overall health. Mounting evidence suggests that developmental exposure to extrinsic factors  leads to pronounced epigenetic and phenotypic effects, commonly referred to as the “developmental origin of health and disease (DOHaD)” Barker, . Epigene12, and zinc , folate (vitamin B9), betaine (trimethylglycine), choline, Vitamin BAnimal model studies have examined how maternal methyl supplemented (MS) diets impact the epigenome and/or phenotypic outcomes in developing offspring Table . Some ofOther factors likely interact with maternal diet to influence the net effect of these diets. Examples include genetic background, sex, developmental windows of exposure, and tissue/cell-specific vulnerabilities, which are discussed below.vy/aA offspring), pregnant a/a female mice exposed to the endocrine disrupting compound (EDC) bisphenol A (BPA) gave birth to a greater percentage of yellow coat color compared to brown coat color (vy/aA) offspring   coat color animals that are concomitantly less prone to these adult diseases. Combined prenatal treatment with a BPA and methyl-supplemented diet in these females was reported to offset the BPA-induced shift in coat color distribution from metabolic deleterious yellow morphs to an increase in brown coat color, healthier offspring  within this allele is hypomethylated, vyA/a status) over several generations (through F5) to increase percentage of pseudoagouti animals possessing a methylated IAP promoter site , an extracellular modulator of bone morphogenetic protein signaling, exhibit midline facial and jaw defects. However, maternal MS diet prevented their jaw defects  promoter  with metabolic disorders, discussed above, and FuAxin mice exhibiting tail dysmorphogenesis, or “kinky” tail  to high concentrations of folic acid resulted in newborn mouse pups exhibiting disrupted cerebral gene expression for transcripts and their protein products implicated in normal neural development  in children  for maternal consumption of prescription prenatal vitamins (containing > 1 mg of folic acid) and ASD incidence in offspring , as well as tissue/cell specificity and concentration and duration of exposure to these nutritional supplements. All of these factors should be considered when employing maternal MS diets to combat fetal disease.Comprehensive long term animal and human epidemiological studies should be undertaken to assess the global effects of these nutraceuticals and to resolve the current conflicting data in regards to maternal MS diet. Until then, women requesting prenatal/perinatal vitamin support should be advised against consuming methyl supplements,  in doses that exceed the current recommendations for preventing fetal neural tube defects.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Salmonella enterica serovar Typhimurium monophasic variant  strains involved in a long-term salmonellosis outbreak that occurred in central Italy in 2013 to 2014.Here, we present the draft genome sequences of 19  Salmonella is a Gram-negative foodborne pathogen distributed worldwide. Even if few lineages have been detected, its antibiotic resistance pattern is very heterogeneous, spanning from multidrug-resistant to largely susceptible strains .Nineteen strains, chosen among clinical and environmental isolates on the basis of their spatial-temporal distribution and familiar kinship, were subjected to whole-genome sequencing together with three unrelated strains as outgroups. Genomic DNA was extracted by Qiagen EasyPrep, libraries were prepared using the Hi-Q sequencing kit, and sequencing was performed on a PGM Ion Torrent platform. Raw reads were submitted to the SRA repository , while bramework  plus somN50 values and GenBank accession numbers.The results from the genome annotation  are summarized in The availability of the assembled sequences allowed us to better understand antibiotic resistance mechanisms and to clarify genomic relationships among the isolates.The sequences described here have been deposited at GenBank under the accession numbers indicated in


The genomic sequences of phages isolated on mycobacterial hosts are diverse, mosaic and often share little nucleotide similarity. However, about 30 unique types have been isolated, allowing most phage to be grouped into clusters and further into subclusters . Many toWe computed tetranucleotide usage deviation, the ratio of observed counts of 4-mers in a genome to the expected count under a null model . Tetranuhttps://github.com/bsiranosian/tango_final.Genome analysis based on tetranucleotide usage shows promise for evaluating host-parasite coevolution and gene exchange within the mycobacteriophage population. These methods are computationally inexpensive and independent of gene annotation, making them optimal candidates for further research aimed at clustering phage and determining evolutionary relationships. Code for genome analysis and data used in this project are freely available at


Upogebia deltaura upon temporal variation in the abundance of genes representing key N-cycling functional guilds. The abundance of bacterial genes representing different N-cycling guilds displayed different temporal patterns in burrow sediments in comparison with surface sediments, suggesting that the burrow provides a unique environment where bacterial gene abundances are influenced directly by macrofaunal activity. In contrast, the abundances of archaeal ammonia oxidizers varied temporally but were not affected by bioturbation, indicating differential responses between bacterial and archaeal ammonia oxidizers to environmental physicochemical controls. This study highlights the importance of bioturbation as a control over the temporal variation in nitrogen-cycling microbial community dynamics within coastal sediments.In marine environments, macrofauna living in or on the sediment surface may alter the structure, diversity and function of benthic microbial communities. In particular, microbial nitrogen (N)-cycling processes may be enhanced by the activity of large bioturbating organisms. Here, we study the effect of the burrowing mud shrimp  Upogebia deltaura and Callianassa subterranea, which are active and abundant decapods that create large, complex burrow systems in marine sediments , bacterial communities exhibited less seasonal change in structure than those communities inhabiting surface sediment  compared with those within tidal flat surface and subsurface sediments  to investigate temporal variation in the abundance of specific bacterial and archaeal genes representing key N-cycling functional guilds within sediment samples taken from the walls of amoA); bacterial denitrifiers (nirS) and bacteria capable of the anammox process (Planctomycetes-specific 16S rRNA). Clone library analysis confirmed the specificity of each of the primer pairs used for subsequent q-PCR. In particular, sequence analysis showed that the Planctomycetes-specific 16S rRNA primers used here specifically targeted anammox bacteria, as shown previously  and ‘sampling month’. Bacterial 16S rRNA and nirS gene abundances showed no significant variation with either sediment category or sampling month. However, the abundances of each of the other genes studied  varied significantly with sampling month  Fig. . The metnirS varied significantly with sampling month, and as for bacterial amoA and anammox 16S rRNA, there was a significant interaction between sampling month and sediment category ; this effect was not evident for surface sediments. We may interpret these differing seasonal patterns in gene abundance within the context of environmental factors known to impact upon microbial community dynamics in coastal sediments.In general, the abundances of all genes in surface sediments were highest in both July 2009 and 2010, and lowest in May, with an additional peak in March Fig.  showed sFor example, variation in microbial community abundance and activity in surface sediments is generally assumed to be driven by changing environmental conditions, such as pH and salinity, or stochastic processes, such as sediment turnover during a storm. On seasonal timescales, the most important regulators of N-cycling functional guild abundance may be temperature, which exerts a major control over all life processes  with the blooming populations of autotrophs has been shown to adversely affect benthic ammonia oxidizing bacteria (AOB) abundance , during irrigation events . Ammonia oxidizing archaea (AOA) have been found in greater abundance than AOB in a variety of benthic marine and estuarine environments  amoA copies per cell  from marine sediments by denitrification (nirS) and anammox. Nr-removal processes play a critical role in coastal sediments, where terrestrial run-off can stimulate eutrophication events in coastal waters, particularly during autumn, when both precipitation rates and the input of agricultural nutrients into estuarine waters are high . The impacts of bioturbation on the activity of the denitrifying bacteria could therefore be an important consideration in future models of the benthic response to coastal environmental change.The activity of amoA target specifically the ‘high-ammonium’ ecotype identified by Sintes and colleagues  is directly influenced by bioturbation activity, and such effects vary between different bacterial and archaeal N-cycling guilds. These data are interpreted with the caveat that the PCR primers used here target specific bacterial and archaeal phylotypes and/or ecotypes; for example, our primers for archaeal lleagues . We alsoS Rusch, . Howevera priori factors used here: sediment category (surface vs. burrow) and sampling month. This study therefore highlights the importance of temporal variation coupled to macrofaunal bioturbation activity in driving microbial community dynamics in coastal sediments. In particular, this study emphasizes the importance of the often overlooked interactions between macrofaunal and microbial communities upon key biogeochemical cycling processes within coastal benthic ecosystems. Our suggestions for the ways in which shrimp behaviour influence gene abundance patterns may act as a useful starting point for future investigations into the environmental controls on microbial functional diversity and activity.It is also worth noting that the presence of a functional gene does not mean that function is operating within the specific environment, and an important continuation to this study would be to identify whether these genes correlate with the relevant biogeochemical rate processes. Nevertheless, we have observed gene abundances that fit within the ranges of previously reported values for these genes in similar marine environments Table  and vary


Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown etiology with a wide range of clinical manifestations. Since CRMO is a systemic disorder that can affect multiple skeletal sites, whole-body imaging techniques (whole body bone scintigraphy -WBBS- or whole body magnetic risonance -WBMRI-) provide major contribution to the initial diagnostic approach, as well as during follow-up.To compare WBMRI with WBBS in the assessment of bone lesions in patients with CRMO.We retrospectively evaluated all WBMRI examinations performed between January 2010 and December 2014 in 18 patients with clinical, laboratory and histology findings suggestive for CRMO.WBMRI were evaluated independently by two experienced paediatric radiologists, who eventually reached consensus. All patients also underwent WBBS within four weeks; WBMRI and WBBS findings were compared. Signal hyperintensity compared with normal bone on STIR images and increased tracer activity in bone delayed scans on WBBS were considered indicative of disease involvement.WBMRI and WBBS showed 225 and 132 lesions, respectively. In the appendicular skeleton, WBMRI demonstrated 143 lesions and WBBS 66 lesions; in the axial skeleton, WBMRI demonstrated 63 lesions and WBBS 18 lesions. WBMRI demonstrated joint involvement in 19 sites and WBBS in 48. The higher concordance between the two methods was observed in the sacroiliac joint (13 lesions for both methods); the higher discordance was observed in spine (WBMRI showed 55 lesions and WBBS 5) and in sterno-clavicular joint (WBMRI showed 2 lesions while WBBS 12).Both WBBS and WBMRI confirmed to be useful tools for the detection of CRMO lesions, as it is reported in literature. Discordance between WBBS and WBMRI is probably due to several factors. In the evaluation of axial skeleton (in particular of the spine), WBMRI shows higher spatial resolution than planar WBBS, but tomographic acquisition (SPECT) enhances the sensitivity of WBBS. Moreover, age-related conversion of hematopoietic marrow to fatty marrow in children may create a confusing appearance on MRI and may be misleading. Finally, in particular in WBMRI performed during treatment and follow-up, clinical relevance of the WBMRI-positive but WBBS-negative lesions is unclear, as still debated in current literature.


Clarkia (Onagraceae) sister taxa. Consistent with our predictions, one outcrosser (C. unguiculata) exhibited faster pollen germination and less variation in pollen tube growth rate (PTGR) among pollen donors than its selfing sister species, C. exilis. Contrary to our predictions, the selfing C. xantiana ssp. parviflora exhibited faster PTGR than the outcrossing ssp. xantiana, and these taxa showed similar levels of variation in this trait. Pollen performance following self- vs. cross-pollinations did not differ within either selfing or outcrossing taxa. While these findings suggest that mating system and pollen performance may jointly evolve in Clarkia, other factors clearly contribute to pollen performance in natural populations.We tested three predictions regarding the joint evolution of pollen performance and mating system. First, due to the potential for intense intrasexual competition in outcrossing populations, we predicted that outcrossers would produce faster-growing pollen than their selfing relatives. Second, if elevated competition promotes stronger selection on traits that improve pollen performance, then, among-plant variation in pollen performance would be lower in outcrossers than in selfers. Third, given successive generations of adaptation to the same maternal genotype in selfers, we predicted that, in selfing populations (but not in outcrossing ones), pollen would perform better following self- than cross-pollinations. We tested these predictions in field populations of two pairs of  The evolutionary and ecological factors that have promoted the diversity of plant sexual reproductive strategies have been a long-standing area of inquiry among evolutionary biologists. The evolutionary transition between outcrossing and selfing, in particular, has received considerable attention, in part because mating system shifts are widespread and have occurred independently within and across numerous taxa ,2,3. IntPollen performance traits are often genetically based ,21,22,23Evidence from studies conducted in natural populations suggests that pollen competition may regularly result in conditions favoring rapid pollen tube growth. First, although pollen limitation has been detected experimentally in many wild plant populations , theRecently, we proposed three predictions regarding the evolution of pollen performance in predominantly self-fertilizing and outcrossing taxa . Our preSecond, because selfing reduces the number of distinct pollen genotypes deposited on individual stigmas, the comparatively stronger opportunity for selection on pollen performance traits in outcrossing taxa should have purged variation in these traits more effectively in outcrossers relative to selfers. Accordingly, we predicted that outcrossing taxa would harbor less genetically based variation among individual pollen donors in pollen performance traits than closely related selfing taxa. This prediction is based on the expectation that intense pollen competition among pollen genotypes will result in selection favoring rapid pollen germination and/or growth in outcrossing taxa. It should also be noted that maternal plant identity and environmental factors such as temperature and resource availability may also contribute to among-donor variation in pollen tube growth and germination in outcrossing taxa ,63,64,65i.e., combinations of alleles at different loci that result in particularly high performance) that influence pollen performance are likely to be reliably and consistently inherited over multiple generations and thus accumulate in populations. In other words, because the pollen of selfers experiences successive generations of pollen germination and pollen tube growth in genetically consistent maternal plant tissue, their pollen should evolve to be particularly well adapted to grow within its parental genotype. By contrast, because outcrossers typically mate with multiple, genetically distinct partners over their lifetimes, such beneficial epistatic interactions are more likely to break down due to recombination, and are therefore less likely to remain stable in outcrossing taxa than selfing taxa. Moreover, outcrossers should experience strong selection favoring the ability of pollen to perform well in a wide variety of stigmatic and stylar genotypes, while selection favoring such tolerance may be comparatively weak in autogamous selfers, whose pollen grains rarely germinate on foreign maternal genotypes. Consequently, we hypothesized that in regularly selfing taxa, pollen should have evolved to perform better following self-pollinations than following cross-pollinations. By contrast, in habitually outcrossing taxa, we predicted that pollen would either perform better following cross-pollinations than self-pollinations  or thats e.g., ,67,68).,68.i.e.,Clarkia tembloriensis (Onagraceae) populations and cultivated in growth chambers provides preliminary support for our predictions. Smith-Huerta . The objective of these analyses was to assess the effect of pollination type on PTGR and the proportion of the style length travelled by viable pollen grains. Therefore, zero values, which were associated with pollen grains that did not germinate or whose tubes failed to enter the style 2.5 hours post-pollination, were excluded from these analyses. Temperature-adjusted performance traits for unguiculata were calculated using the residuals from linear regressions in which a given pollen performance trait (PTGR or the proportion of the style traveled) was regressed on temperature at the time of pollination (°C). For xantiana and parviflora we used the residuals from polynomial regressions in which a given measure of pollen performance (PTGR or the proportion of the style travelled) was regressed on (temperature at style harvest) and (temperature at style harvest)2 because these regressions gave a better fit than the linear regressions. See 2r values associated with these models. For the Stark Creek exilis population, we controlled statistically for the effect of temperature by using the residuals from polynomial regressions in which PTGR or the proportion of the style traveled was regressed on temperature at the time of pollination (°C) and (temperature at the time of pollination)2. See 2r values associated with these models. For each taxon, variance components associated with the random effects of Pollen Donor and Pollination Type nested within Pollen Donor were estimated using the REML method for each temperature-adjusted pollen performance trait. For unguiculata, xantiana,and parviflora, we conducted these two-factor analyses after initial models including three random effects  indicated that pollen performance did not differ significantly between populations of the same species or subspecies. The 95% confidence intervals spanning the variance components associated with the Population effect included zero. All analyses were performed using JMP 9.0 (SAS Institute).We calculated Clarkiaexilis and its outcrossing sister species, C. unguiculata, in a manner that is consistent with the hypothesis that pollen competition promotes the evolution of rapid pollen performance in outcrossing taxa relative to their selfing counterparts. Plants from unguiculata populations exhibited faster or more frequent pollen germination than plants from exilis populations; unguiculata pollen tubes were more likely to have entered the style within 2.5 hours of pollination. Surprisingly, we found that C. xantiana ssp. parviflora exhibited faster PTGR and greater proportional distance travelled within the style than its outcrossing counterpart, C. xantiana ssp. xantiana. These contrasting patterns suggest that gamethophytic evolution following mating system transitions is likely to involve a variety of genetic and ecological factors. The extent to which the evolution of pollen performance traits is influenced either by local environmental conditions or by strong correlations with plant traits other than mating system in the Clarkia taxa studied here, however, merits further investigation. Case studies evaluating additional pairs of sister taxa are needed before generalizations regarding the joint evolution of mating system and pollen performance can be made. Nevertheless, the contrasting patterns that we observed in the two pairs of Clarkia sister taxa are likely driven in part by differences in the magnitude of gametophytic competition in unguiculata and xantiana populations. In populations characterized by consistent pollen limitation, such as xantiana, selection on pollen performance traits may be weak or neutral. Consequently, this study highlights the importance of evaluating the joint evolution of pollen performance and mating system in field populations, where abiotic and biotic ecological factors may influence the phenotypic expression of and ultimately the evolution of sexually selected traits. Differences between selfers and outcrossers in the diversity of potential pollen donors that arrive on stigmas have been predicted to drive the evolutionary divergence of sexually selected traits, such as the speed by which pollen grains germinate and travel through the style. Here we demonstrate that pollen performance differs under field conditions between


Patients with chronic renal failure may develop sensorineural hearing loss. Cochlear implantation has rarely done after organ transplantation. Herein, we report on a 33-year-old kidney transplantation recipient who underwent cochlear implantation for her progressive sensorineural hearing loss in Khalili Hospital Cochlear Implant Center, affiliated to Shiraz University of Medical Sciences. The implantation was done successfully with no complications. Cochlear implantation may be an appropriate therapeutic option for sensorineural hearing loss caused by chronic renal failure. Cochlear implantation has revolutionized the treatment of profound hearing loss. This procedure is relatively safe and it becomes the treatment of choice for both children and adults. Most of the patients reported improved quality of life, speech recognition and communication. Recently, patients with chronic diseases like chronic renal failure with hearing impairment, have also considered for cochlear implantation. Chronic kidney disease may result in high frequency sensorineural hearing loss (SNHL). The probable causes include uremia , congeniA 15-year-old Iranian girl developed chronic renal failure due to post-streptococal glomerulonephritis. Although she was on maintenance hemodialysis for seven months, she developed end-stage renal disease and underwent living non-related kidney transplant in 1992. One month later, she was treated for pleural effusion and pneumonia and received the ototoxic drug, amikacin for several weeks and developed bilateral progressive SNHL confirmed by pure tone audiometry and auditory brainstem response audiometry. She was then referred to our center and received a powerful hearing aid which was not successful to increase her speech awareness threshold. Therefore, she was considered for cochlear implantation. Before performing the procedure, multidetector high resolution computed tomography of temporal bone revealed normal anatomy of the temporal bone including mastoid, middle ear, inner ear and internal auditory canal with no evidence of mastoiditis or pathologic findings. The cochlear turns in both sides appeared normal with normal semicircular canals. After evaluation, the right ear was selected for the implantation. An advance bionics prosthesis (HiRes 90 K) was used and the active electrode was inserted fully in an appropriate position in the year 2011. After the operation, the patient was hospitalized in the ENT ward for 24 hours and discharged in good condition with antibiotics. She continued her routine immunosuppressant drugs till now without any signs of wound infection or other complications.Hearing aids are the principle means of auditory rehabilitation for patients with SNHL. Hearing aids also have important roles in the management of conductive hearing loss. Implantable hearing aid has several advantages for patients with hearing loss such as increasing gain and dynamic range, reducing feedback, reducing maintenance, improving appearance and being free to occlude one of the ear canals . CochleaHearing loss is one of the most common debilitating conditions in patients who begin renal replacement therapy. The incidence of hearing loss in children is 8.6% . The effFor cochlear implantation, immunosuppressive drugs can be continued preoperatively without dose adjustments , 5, 9. FWe concluded that cochlear implant may help properly selected renal transplant recipients with SNHL.


Mungos mungo), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established.Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this ‘stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose ( The stress-related suppression hypothesis proposes that dominant females suppress subordinate reproduction through behaviours that lead to chronic elevations in circulating glucocorticoids (GCs) and consequent reproductive downregulation –4. Notabin utero or early post-natal development and affect offspring health, condition and survival [While socially induced GC elevations have frequently been considered a potential cause of reduced conception rates among subordinates, they also have the potential to compromise the outcomes of established pregnancies. For example, elevated GCs during pregnancy may impact survival ,7. Whilesurvival ,8, whethMungos mungo). Banded mongooses live in stable cooperatively breeding groups comprising a ‘core’ of breeding adults  that reproduce three to four times per year, alongside a subset of younger individuals that breed occasionally [Here, we test these three predictions with a detailed investigation of faecal glucocorticoid (fGC) concentrations and reproductive success in female banded mongooses  between December 2010 and April 2014. All animals were marked and habituated to close observation (less than 5 m). Groups were observed every 1–4 days to record all breeding events. We ran generalized linear mixed models (GLMMs) using the lme4 package  with PoiPregnancy can be detected at around 40 days by swelling of the abdomen  and birtWe collected 218 faecal samples from 35 females prior to and during gestation . Full details of sample collection and hormone analysis including validations are given in . In brie(a)We calculated three measures of reproductive success for each female recorded as having given birth: (i) the number of fetuses, (ii) the number of emergent offspring, and (iii) the proportion of fetuses surviving to emergence. We fitted each of these three measures as a response variable in GLMMs. Rank (determined by ranked age following ) was fit(b)We fitted fGC concentrations as a response variable in a GLMM with rank as the main predictor of interest. As GC concentrations may vary within a breeding attempt, we also fitted an interaction between rank and stage of pregnancy  as well as fixed effects of female age, group size, rainfall and pre-conception body mass to control for other factors which may contribute to fGC variation.(c)We fitted the number of emergent offspring and the proportion of fetuses surviving to emergence as response variables in two separate GLMMs with fGCs during the third trimester as the predictor of interest. We focused this analysis on fGCs in the third trimester because that is when we saw the clearest difference in fGCs between low- and high-ranking females.3.p = 0.041; figure 1a) and the proportion of fetuses surviving to emergence . There was no effect of rank on the number of fetuses carried by a female (p = 0.87). We found a significant interaction between female rank and pregnancy stage on fGC concentrations: lower ranking females did not differ from higher ranking females prior to conception or during the first trimester but had elevated fGCs during the second and third trimesters  and a lower proportion of their fetuses survived to emergence . Full model outputs are included in the electronic supplementary material S1.Lower ranking females that carried to term experienced lower reproductive success than higher ranking females, both when measured as the number of assigned offspring , both when measured as the proportion of fetuses surviving to emergence and the number of emergent offspring. Although higher and lower ranked females had similar fGC concentrations prior to gestation and during the first trimester, lower ranked females showed significantly elevated fGC concentrations during the second and third trimesters. These results highlight the possibility that stress-related suppression of subordinate reproduction arises through gestational effects that compromise offspring survival either during the latter stages of pregnancy or soon after birth (prior to emergence from the burrow). Accordingly, females that experienced higher fGC concentrations during the third trimester had fewer emergent pups and a lower proportion of fetuses surviving to emergence.in utero, this rank-related difference in reproductive success could well have arisen from pre-natal developmental impacts on offspring survival either during late pregnancy or during the early post-natal period. A role for rank-related maternal stress during late gestation in generating these effects on offspring survival would be consistent with experimental evidence that late-gestational GC elevations can inhibit offspring development [Rank-related differences in reproductive success among female mammals commonly occur due to differences in conception rates, either because subordinate females exercise reproductive restraint or because their ability to conceive is compromised by active interference by dominant females ,19. By celopment ,20. In telopment , play a per se. However, the gestational GC elevations of lower ranked females could arise at least in part from energetic differences during gestation. For example, subordinates may be competitively excluded from resources by dominant females. Alternatively, as intra-sexual conflict among females may frequently be resolved without overt physical conflict, these GC elevations could also reflect responses to more subtle rank-related outcomes, such as social isolation [The stress-related suppression hypothesis posits that elevated GC concentrations observed in lower ranking females are a result of aggression from dominant females. However, conspicuous aggression among female banded mongooses is rare outside of eviction events . As suchsolation . Either


How receptions of sensory inputs information turn into perceptions in our brain? To address these questions, we proposed method reconstructs the neuronal tracts by applying the shortest path graph algorithm between functional regions in the Drosophila brain. With these neuronal tracts, we analyze and draw a network diagram of projection neurons (PNs) relaying sensory input to higher brain centers in the Drosophila brain. Drosophila is a widely used genetic model system for understanding human biology ,2. WhileThe network diagram shows hierarchical structure, small-world characteristics, and is composed of functional modules corresponding to the sensory modalities. This ultimate goal of such an atlas is to identify connectivity between neurons for understanding the function/circuit relationships.


Improving NK cell persistence in vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic.Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression  Natural killer (NK) cells are immune cells primarily found in the blood, liver, spleen, bone marrow, and to a lesser extent, in lymph nodes . They weNK cells can mediate cytotoxicity via multiple distinct mechanisms. Degranulation is the most studied cytotoxicity pathway, where NK cells release cytotoxic granules upon contact with the target. Cytotoxicity via this pathway is dictated by a balance of signals from an array of germline encoded activation and inhibitory cell surface receptors. Most activation receptors need simultaneous co-stimulation by other activation receptors to trigger NK cell cytotoxicity . One excin vivo persistence, and doubts regarding their ability to migrate to tumor tissues following adoptive infusions. Although recent data have shown CMV reactivation reduces the risk for AML relapse following HSCT  following hematopoietic stem cell transplantation (HSCT) and that adoptively infused mature donor NK cells could induce remission in AML patients , 10. Desing HSCT  potentiain vivo holds potential to advance the efficacy of NK cell-based cancer immunotherapy. However, until relatively recently, the genetic manipulation of NK cells has proven to be challenging. Viral transduction, successfully used for T cells, has been associated with low levels of transgene expression and unfavorable effects on cell viability when used with NK cells. Recent optimization of viral transduction and the establishment of electroporation technologies for efficient gene transfection have revived the enthusiasm for studies evaluating genetic modification of NK cells. Investigators around the world are now exploring the potential of multiple different NK cell modalities to genetically reprogram with the overall aim of further improving upon their capacity to kill tumors in cancer patients. One example of how this technique can be utilized is to introduce genes into NK cells coding for gamma-cytokines (IL-2 and IL-15) to induce independence from the obligate need of exogenous cytokines for proper in vivo persistence and expansion post infusion. This and similar strategies may further improve the efficacy of NK cell-based immunotherapy, as tumor regression following adoptive NK cell infusions in AML patients has been reported to be dependent on their ability to expand in vivo  resulted in an average 69 and 71% transduction efficiency, respectively .More recently, studies evaluating transduction of NK cells using lentiviral vectors have been pursued. In contrast to transduction with retro- and adenoviral vectors, lentiviral vectors can incorporate transgenes into the genome of non-dividing cells. Further, lentiviral vectors allow for gene modification of NK cells without altering their phenotypic and functional properties as occurs following stimulation with i.e., cytokines. The first report on the successful use of lentiviral vectors for genetic modification of NK cells was performed in primary murine NK cells , with suIn summary, viral transduction of NK cells results in variable transduction efficacies and may require multiple rounds of transduction and/or post transduction cell enrichment to achieve acceptable transgene expression. Further, viral associated cell death and the need for post-transduction enrichment may compromise the clinical utility of this approach. Finally, although the risk may be low, the possibility of viral-induced insertional mutagenesis and immunogenicity , 44 occuelectroporation (including nucleofection) or lipofection. Since the latter has been used only in a few studies  human NK cells  and the transcription activator-like effector nucleases (TALEN) technologies, the recently developed clustered regularly interspaced short palindromic repeats (CRISPR) technique has rapidly become a popular tool for targeted gene integration . The CRIin vivo persistence and expansion, tumor tissue migration, and the tumor targeting capacity of adoptively infused NK cells  donors were found to have substantially augmented ADCC following electroporation with mRNA coding for the HA-CD16  compared to those who carry the low-affinity CD16-158F (LA-CD16) polymorphism , 66, sev LA-CD16 . Recentl HA-CD16 . These dIntroduction of genes that render NK cells insensitive to suppressive cytokines such as TGF-β, thereby preserving their cytotoxicity, has also been studied. Yang et al. generated an NK-92 cell line resistant to the suppressive effects of TGF-β by genetically modifying them to express the dominant negative mutant form of TGF-β type II receptor (DNTβRII) on their surface . Adoptivin vitro and in a preclinical mouse model  exploiting the role for CAR19-expressing Genetic engineering of NK cells to make them cytokine independent and thereby improve persistence, while boosting their cytotoxic capacity, may be one avenue to further explore. The advantage with this approach would be that exogenous cytokines would be unnecessary following NK cell infusion, which may reduce the risk of mobilizing regulatory T cells that directly suppress NK cell cytotoxicity . Challenin vivo homing of infused gene engineered NK cells have yet been published.Migration to the tumor tissue is another aspect governing proper tumor targeting. This aspect has been largely overlooked and could potentially improve clinical outcome if infused NK cells are redirected to the tumor site instead of circulating non-specifically into mostly non-tumor-bearing tissues. No studies aimed at improving the in vitro have been explored. Introduction of CARs represent the most studied and developed approach that has recently reached clinical evaluation , thereby giving genetically reprogramed NK cells an additional layer of target specificity. However, many additional preclinical studies will be needed before these approaches can reach clinic.As discussed above, numerous strategies for redirecting or boosting NK cell tumor killing on Table . Expressex vivo manipulation.The choice of method for genetic reprograming of NK cells is another important factor that needs to be considered when taking genetically engineered NK cells to clinical evaluation. Viral transduction has the advantage of stable expression; however, as mentioned above, viral transduction of NK cells, especially primary cells, does not always lead to a satisfactory level of transgene expression and may require multiple rounds of transduction followed by selection of transgene positive cells. Moreover, proper expression of transgenes induced by viral transduction can take days, which may be of disadvantage since the lifespan of an NK cell may be relatively short following adoptive transfer . Future studies are warranted to better understand if multiple infusions of transfected NK cells can compensate transient transgene expression or if stable transgene expression is a prerequisite for inducing clinical responses following adoptive transfer of genetically engineered NK cells. Studies are also needed to fully understand the lifespan of NK cells, particularly those that have undergone in vivo (ex vivo for clinical infusion (The optimal method for genetic manipulation of NK cells to be used in a clinical trial may also depend on what NK cell preparation is used Box . The advin vivo . Moreoveinfusion . IdeallyBox 3Anti-tumor antibodies and CAR T cells have established immunotherapy as a viable treatment option for patients with cancer. Given their rapid and efficient method of recognizing tumor cells, NK cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Viral transduction of NK cells initially resulted in low transgene delivery efficiencies that often required multiple rounds of transduction and/or cellular enrichment to achieve acceptable numbers of transgene expressing cells. Nevertheless, recent improvements in retro- and lentiviral transduction of NK cells have led to a flurry of preclinical studies on gene engineered NK cells. A number of studies have also shown that NK cells can be genetically reprogramed using mRNA electroporation. In contrast to viral transduction, this approach offers high transfection efficiencies without compromising their viability and does not require high-level biosafety laboratories. Although promising preclinical data on mRNA electroporated NK cells have emerged recently, concerns have been raised regarding the clinical utility of this approach as it only results in transient transgene expression.in vivo, and with rapid developments in clinically compliant techniques to genetically manipulate NK cells, we foresee genetic engineering as an obligatory pathway to exploit the full potential of adoptive NK cell immunotherapy in patients with cancer.Recently initiated clinical trials will soon give insight into the potential effectiveness of cell-based cancer immunotherapy strategies that utilize genetically modified NK cells. Nevertheless, further optimization of both viral transduction and electroporation of NK cells is still needed before this approach can be fully exploited in the clinic. With the recent advances in our understanding of the complex biological networks that regulate the capacity of NK cells to target and kill tumors The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mitochondrial fusion-fission dynamics play a crucial role in many important cell processes. These dynamics control mitochondrial morphology, which in turn influences several important mitochondrial properties including mitochondrial bioenergetics and quality control, and they appear to be affected in several neurodegenerative diseases. The molecular machineries behind mitochondrial fusion and fission events are relatively well known. The regulation of fusion and fission events beyond the molecular machinery involved is less clear, fusion and fission are not random occurrences but form a cycle whereby fission typically follows fusion. Mitochondrial fission machinery may somehow sense mitochondrial length and become active when the mitochondrion is oversized and cease when mitochondria are smaller. In contrast, mitochondrial fusion events depend heavily on mitochondrial trafficking. Fusion only takes place when two mitochondria meet and motile mitochondria will be more likely to encounter one another. In cultured cortical neurons, for example, only one in every 14th contact between mitochondria results in fusion. The purpose of this presentation is to provide insight into the complex crosstalk between different processes involved in mitochondrial fusion-fission dynamics and to discuss the potential physiological purpose of mitochondrial fusion and fission.


Numerous complex regulatory mechanisms influence the development and function of the peripheral and central nervous system. Among them, hormones belong to the most potent regulatory factors. Various particles known for their hormonal activity serve as neurotransmitters. Additionally, hormones secreted systemically modulate the function of the nervous system both on the brain level and in peripheral organs. Thyroid function has been shown to play a crucial role in the proper cognitive development but also in many other aspects of nervous system activity, in mechanisms involving direct interaction with intrinsic regulatory circuits or indirectly by systemic effects exerted e.g. on the circulatory system or metabolic pathways. Due to these close relations with the nervous system function, disturbances of thyrometabolic state are associated with a vast spectrum of neurological signs and symptoms including: mood and cognitive disorders, headache, ophthalmoplegia, tremor and other movement disorders, muscle weakness etc. Both hyper- and hypothyroidism may cause psychiatric symptoms like depressive or anxiety disorder, memory deficits, executive inability and even psychosis. The severe decompensated hypothyroidism may result in myxoedema coma - a life-threatening condition with sequentially progressing encephalopathic symptoms. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAAT) represents another form of encephalopathic disorder associated with thyroid disease and causing potentially serious clinical complications. In the periphery, the thyrometabolic disturbances may affect muscle function resulting in subjective tiredness and low exercise tolerance and in some cases  in objective myopathic signs. Also peripheral nervous system may be affected, mainly in hypothyroid patients, with greater tendency to develop peripheral polyneuropathy and entrapment neuropathies such as carpal tunnel or Guyone canal syndromes.Importantly, the autoimmune thyroid disease has been shown to coexist with other autoimmune processes which may potentially cause neurological symptoms such as myasthenia, Guillain-Barre syndrome or pernicious anaemia. Such conditions have to always be taken in consideration as differential diagnoses in patients presenting with neurological signs and symptoms associated with thyroid disease.


Coronary stent fracture is a known complication of coronary arterial stent placements. Multiple long-term risks are also associated with drug eluting stents. 64-slice multidetector CT (MDCT) coronary angiography has been shown to detect poststent complications such as instent stenosis, thrombosis, stent migration and stent fractures. We report a case of stent fracture in a patient who underwent RCA stenting with associated RCA perforation and almost complete thrombosis of the RCA and peristent fibrinoid collection. This is a rare case of stent fracture with perforation of the RCA. The paper highlights the role of 64-row multidetector computed tomography (MDCT) in evaluation of such poststent placement complications. Stent fracture (SF) has been suggested as one of the leading risk factors of thrombosis and instent restenosis (ISR) in patients who have intracoronary drug-eluting stent (DES) implants ; howeverA 65-year-old male patient presented with a tuberculous knee joint effusion and occasional chest pain. He also had a drug eluting stent inserted in the mid RCA, two years back. However, the patient had recurrent angina within a month of stent placement. A catheter angiography done at that time revealed total occlusion of the RCA stent, with grade III collaterals. He was now referred to our department with a request for CT chest to exclude pulmonary tuberculosis. The CT chest revealed no signs of pulmonary tuberculosis but revealed an irregular localised pericardial fluid collection along the RCA stent . A dedicStent fracture is an important and potentially serious complication of drug-eluting stents (DES) . IncreasNakazawa et al. have graded stent fractures into five categories  and conc64-slice CT coronary angiography is an extremely fast and accurate imaging modality available for the evaluation of stents and their complications. It is found to be more sensitive in detecting stent fractures than conventional catheter angiography. Besides demonstrating in-stent thrombosis, it can effectively evaluate stent fractures, migrations, buckling, or collapse; rare complications such as perforations and aneurysms. This is a rare case of long standing stent fracture with RCA rupture and associated in-stent total occlusion and highlights a unique complication of stent placement: stent fracture causing coronary arterial rupture and subsequent stent migration. It also highlights the utility of 64-row MDCT imaging in effectively demonstrating such serious complications; which may or may not be convincingly shown on conventional catheter angiography.


In contemporary oncology practices there is an increasing emphasis on concurrent evaluation of multiple genomic alterations within the biological pathways driving tumorigenesis. At the foundation of this paradigm shift are several commercially available tumor panels using next-generation sequencing to develop a more complete molecular blueprint of the tumor. Ideally, these would be used to identify clinically actionable variants that can be matched with available molecularly targeted therapy, regardless of the tumor site or histology. Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions. The uniqueness of these tests from other genomic applications used to guide clinical treatment decisions lie in the sequencing platforms used to generate large amounts of genomic data, which have their own related issues regarding analytic and clinical validity, necessary precursors to the evaluation of clinical utility. The generation and interpretation of these data will require new evidentiary standards for establishing not only clinical utility, but also analytical and clinical validity for this emerging paradigm in oncology practice.  Traditional pharmacogenomic applications used to direct molecularly targeted therapy rely on testing tumor tissue for a single genomic marker followed by using tumor-marker specific therapy. There are several established pharmacogenomic applications that are used clinically to aid in treatment decisions for breast, colon, lung and other solid-tumor cancers Table 1). With advances in high-throughput –omic technologies and plummeting costs of next-generation sequencing (NGS), researchers have begun to move beyond testing single genes, to multi-gene panels, to sequencing the entire human cancer genome in order to better understand the underlying molecular pathways driving tumorigenesis. With adClinically available NGS tests are used to characterize an individual’s cancer genome through targeted sequencing of pre-specified candidate genes believed to provide clinically actionable molecular targets. Using a single test to detect a broad spectrum of genomic alterations in the biological pathways from a single biopsy is thought to be a more efficient treatment decision process than the single-marker single-treatment approach,,An established clinical test integrating NGS technology for tumor DNA sequencing requires a standardized protocol with details describing pre-analytic, analytic and post-analytic processes. The pre-analytic variables include the patient’s clinical characteristics as well as details describing the collection and preparation of tumor samples. The analytic variables that may affect the precision and accuracy of the targeted sequencing of pre-specified molecular targets  refer to the actual sequencing process itself and are related to the specific NGS platform used to conduct the massively parallel sequencing as well as individual laboratory procedures. The post-analytic variables  relevant to NGS include variant calling, functional and clinical interpretation, reporting results to clinicians, and data storageThe expanded reach of NGS platforms provides researchers with a much more comprehensive picture of a tumors genomic architecture. In an effort to leverage the technical advances in sequencing technology and expanded vision of a tumors molecular signature several NGS platforms have been integrated into commercially available solid-tumor sequencing panels to identify clinically actionable variants (Table 2). Despite the lack of consensus as to what constitutes a clinically actionable variant, three general categories may be used to classify variants: 1) variants linked to an FDA-approved drug within a specific tumor type; 2) variants linked to an FDA-approved drug outside of the patients specific tumor type; 3) variants linked to non-FDA approved drugs in preclinical testing or early phase clinical trialsTo date, the application of multi-marker tumor panels using NGS has primarily focused on individuals with advanced metastatic disease who have exhausted standard therapies for their particular condition. In such cases, these tests may provide unconventional therapeutic options against an otherwise refractory disease. It is unclear at what point this testing and treatment strategy will become a part of the standard molecular profiling of newly diagnosed malignancies, expanding the potential population impact. As evidence emerges on driver-mutations common across a number of cancer types, newly developed molecularly targeted therapies will provide a means to improve cancer treatment outcomes across a number of cancers with common biological/molecular mechanistic pathways. A more complete picture of an individual’s tumor genome may also be integrated within existing frameworks including age, disease burden, and histologic/molecular features for developing more effective cancer treatment and management strategies-This approach to cancer therapy has received widespread interest from patients, healthcare providers and payersIn a working paper, UnitedHealth spoke to the larger contextual issues of using molecular testing in clinical oncology. A broad emphasis was placed on the expanding opportunities for molecularly targeted therapy using tumor genome sequencing and for improving the process of determining the effectiveness of molecular testing-The analytic workflow of FoundationOne™, hybrid-capture libraries sequenced with Illumina HiSeq2000, was shown to have an analytic sensitivity between 95% and 99%  and a positive predictive value greater than 99% using pooled cell lines as the reference standard ,There appears to be consistency in the pre-analytic factors across the commercially available tests related to tissue sample requirements, collection and preservation (Table 2). All the organizations listed in Table 2 report the sequencing is done in Clinical Laboratory Improvement Amendments (CLIA) certified facilities. While this does provide a limited amount of standardization, the fundamental requirements to establish analytic validity requires a reliable reference standard to align and annotate massively parallel sequence dataTable 3 shows the vast array of molecular targets included in the commercially available tumor panels, with only 34 genes included in all three tests . FoundationOne was reported to detect at least one clinically actionable variant in 76% of samples (N=2200) with an average of 1.57 clinically actionable variants detected per sample (range: 0 to 16)There is a growing body of evidence identifying genomic alterations common across multiple cancer typesBenefits At this time there is no evidence of improved treatment outcomes from using the tests described in Table 2 to direct molecularly targeted therapy in solid-tumors. In addition to the absence of evidence of clinical utility for the commercially available tests, there is also a need to further explore the validity and utility of the underlying hypothesis driving the development and implementation of these tests. One challenge in developing studies investigating the general hypothesis as well as establishing clinical utility is the limited generalizability due to diversity in the evolving panel composition and variation in the clinical interpretation and treatment recommendations . There is a need to standardize the composition of panels and develop standard criteria for classifying variants as clinically actionable. It may also be necessary to prioritize specific variant/therapy combinations when multiple variants with associated therapies are identified, as there may be overlapping toxicities and drug-drug interactions. Characteristics of studies investigating clinical utility, including molecular heterogeneity of study participants as well as specific study designs will also impact generalizability.HarmsNone of the test descriptions included details of patient consent or how incidental findings would be communicated to clinicians or patients. As these tests are intended to be implemented at the point of care, such protocols may be left to the ordering physician and their home institution to determine processes for informed consent, delivery of appropriate pre-test genetic counseling, and disclosure of incidental findings. Given the analytic workflow of the available tests (Table 2) and diverse panel composition (Table 3) it is uncertain how the ACMG recommendations,Another potential harm from implementing this testing and treatment strategy arises from uncertainty in the cost-benefit ratio of the off-label use of expensive chemotherapeutic drugs. As mentioned previously, these tests are currently being offered to patients with advanced disease in whom time spent delivering ineffective therapy may pose a significant risk as a wasted opportunity. Many of the available drugs are associated with well characterized adverse effects (e.g. cardiotoxicity from the kinase inhibitors)Several ongoing clinical trials have incorporated the commercially available tests (Table 4). Designed as feasibility assessments, two non-randomized trials are using FoundationOne (Foundation Medicine) to identify participants with metastatic breast cancer (IMAGE)Recent advances in sequencing technology provide new opportunities for genomic medicine. With these opportunities come the promises of personalized medicine that are changing oncology practice. However, aspects of analytic and clinical validity and clinical utility of the current paradigm shift has yet to be clearly established. Developing the necessary evidence to establish clinical validity and utility may require novel thinking to adapt to the dynamic challenges associated with implementing NGS tumor sequencing into clinical practice. Researchers must also address several limitations in the underlying concepts of this approach including patient selection, analytic workflows, characteristics of the tumor panels (performance characteristics and panel composition), study design, and outcome selection. Several ongoing clinical trials are investing both the feasibility and utility of incorporating NGS technology into clinical practice and will help define the evidentiary standards for evaluating such tests.The GAPP Knowledge Base (GAPP KB) was searched using the term “next-generation sequencing” to identify commercially available multi-marker solid tumor tests using NGS technology. A Google search supplemented the GAPP KB search for eligible tests as well. The following search string was used to search PubMed to identify relevant systematic reviews and guidelines:(((neoplasms/therapy[mesh]) OR (neoplasms/genetics[mesh]) OR (neoplasms/diagnosis[mesh])) AND  OR (molecular targeted therapy/methods[mesh]) OR (genetic testing[mesh]) OR )) AND (humans[mesh])In addition to searching PubMed, the commercially available tests websites were searched to identify relevant literature pertaining to the analytic validity, clinical validity, and clinical utility of the respected test. Ongoing studies were identified in clinicaltrials.gov by searching on the trade name of each commercially available test and company offering the tests described in Table 2. This was supplemented by using the term “next-generation sequencing” to identify additional studies not using any of the tests listed in Table 2.