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interestingly , some evidence has emerged that new - onset diabetes may be a symptom caused by early occult pancreatic cancer [ 2 , 3 ] .
epidemiologic , clinical , and in vitro studies support the hypothesis that pancreatic cancer - associated diabetes mellitus is a paraneoplastic phenomenon caused by diabetogenic tumor - secreted products . in vitro studies and animal models
further suggest that beta cell dysfunction in pancreatic cancer leads to an impaired response to oral glucose load , hyperglycemic clamp , and glucagon stimulation .
it is possible that new - onset diabetes associated with pancreatic cancer is due to a combination of beta cell dysfunction and an increased insulin resistance [ 1 , 3 ] . the presentation of pancreatic cancer depends largely on tumor location .
carcinomas in the region of the ampulla and pancreatic head tend to present earliest with signs and symptoms of biliary tree obstruction , while tumors of the body and tail tend to present later as palpable swelling . other common presenting symptoms of pancreatic cancer are malaise , anorexia , weight loss , and upper abdominal pain .
this case report serves to emphasize the role of new - onset diabetes in certain patients as a warning sign necessitating further investigation for a specific etiology , including pancreatic cancer .
new - onset diabetes associated with specific risk factors may prompt for early testing , detection , and treatment of pancreatic cancer .
however , due to the low prevalence of pancreatic cancer , clear guidelines in terms of screening measures even in high - risk patients would be needed . in short ,
the learning objectives of the present case report are ( 1 ) to review the epidemiology and presentation of pancreatic adenocarcinoma , ( 2 ) to examine the associations between type 2 diabetes and pancreatic adenocarcinoma , and ( 3 ) to illustrate that new - onset diabetes in the setting of risks for pancreatic cancer may be a clue that the patient needs workup for this malignancy .
a 53-year - old african american female with a medical history significant for stage ib , grade 1 endometrial adenocarcinoma status - post total abdominal hysterectomy and bilateral salpingoophorectomy 7 years ago presented to the henry ford hospital emergency department upon instruction from her oncologist after her serum glucose was found to be severely elevated .
she had no history of diabetes with fasting blood sugars < 126 as recent as 6 months prior to presentation .
she was experiencing polydipsia and polyuria for 3 weeks with associated blurry vision and distal extremity paresthesias .
six months prior to presentation , she began experiencing persistent , non - exertional , left - sided chest wall pain .
her family history was significant for type 2 diabetes and hypertension , but she denied a family history of any cancers .
laboratory findings on admission were significant for serum blood glucose 608 mg / dl , white blood cell count 11.9 k/l , bicarbonate 27 mmol / l , anion gap 10 , and beta hydroxybutyrate 0.13 mmol / l .
further laboratory studies were significant for an elevated ca 19 - 9 ( 349.9 u / ml ) , normal ca-125 ( 15 u / ml ) , and normal c - peptide ( 1.4 ng / ml ) .
a bone scan for the persistent left - sided chest pain performed shortly after admission was concerning for increased uptake in the left scapula and l5 vertebral body .
the patient subsequently underwent a ct scan of the chest , abdomen , and pelvis with iv contrast that showed a 3.6 2.5 cm mass extending from the body into the tail of the pancreas and a single 1-cm low attenuation lesion in the liver with minimally enlarged hepatic and portacaval lymph nodes .
a biopsy of the hepatic lesion was performed and was suggestive of metastatic pancreatic adenocarcinoma ( fig .
pathology showed neoplastic glands surrounded by prominent desmoplastic stroma and lined by cuboidal epithelium with marked nuclear pleomorphism , loss of polarity , and frequent apoptotic bodies .
the tumor cells stained positive for cytokeratin 7 and 19 and stained negative for estrogen receptor and cytokeratin 20 .
these findings , along with the newly discovered pancreatic mass , were consistent with stage iv adenocarcinoma of pancreatobiliary origin .
after extensive discussion with the patient and her family , she decided to proceed with the folfirinox chemotherapy regimen for palliative purposes .
her diabetes was treated with a regimen of lantus 50 units once daily and with aspart 15 units before meals .
she has completed four cycles of chemotherapy and has been experiencing elevated blood sugars despite compliance with her insulin regimen .
in our patient , new - onset type 2 diabetes was a harbinger of her undetected pancreatic adenocarcinoma . if it had been detected earlier , it may have prompted clinicians to look more closely for pancreatic pathology in the setting of new - onset bone pain .
her cancer was only discovered after a workup for persistent musculoskeletal pain with nuclear bone scan imaging that showed evidence of metastatic disease . in this case
, we can not definitively state whether pancreatic cancer or diabetes came first , but evidence demonstrates that new - onset type 2 diabetes may be a presenting symptom of pancreatic cancer in some patients .
earlier detection of her diabetes , especially in the context of unexplained musculoskeletal pain and weight loss affecting multiple sites , may have prompted further testing for pancreatic adenocarcinoma .
pancreatic adenocarcinoma carries a poor prognosis since diagnosis is typically made at advanced stages of disease due to delayed onset of symptoms .
recent studies have shown that up to 80% of the patients diagnosed with pancreatic cancer show glucose intolerance , and that pancreatic cancers found at the onset of diabetes are more likely to be resectable . in an attempt to minimize unnecessary testing ,
patients with new - onset diabetes plus classical risk factors for pancreatic cancer including age , bmi , and family history should be evaluated with blood tests for the tumor markers cea and ca19 - 9 , both of which have shown a positive correlation with diabetes - associated pancreatic cancer .
screening all patients with new - onset diabetes for pancreatic lesions would not be cost - effective or efficacious , but further research should be done to identify the patients with new - onset diabetes who should be screened further . | pancreatic adenocarcinoma has an incidence rate nearly equal to the mortality rate and is the fourth leading cause of cancer - related death in the usa .
this is largely due to late symptom onset and diagnosis .
evidence has emerged that new - onset diabetes may be a symptom caused by occult pancreatic cancer .
we report the case of a middle - aged african american female who presented with hyperglycemia and persistent scapular tenderness .
she was subsequently diagnosed with new - onset diabetes and metastatic pancreatic cancer confirmed by liver biopsy .
she did not have diabetes or pre - diabetes in the 6 months prior to presentation .
the following report will serve to emphasize the role of new - onset diabetes in certain patients as a warning sign necessitating further investigation for pancreatic cancer .
new - onset diabetes associated with specific risk factors may prompt for early testing , detection and treatment of pancreatic cancer . | Background
Case Presentation
Discussion |
the abdominal cocoon is an infrequently encountered cause of intestinal obstruction that was was first observed by owtschinnikow in 1907 , and later , termed the cocoon by foo in 1978 .
the exact aetiology of this entity ( also called scerosing encapsulating peritonitis ) is by and large unknown ( the idiopathic / primary variety of cocoon ) , but at times , cocoon formation can occur secondary to a variety of conditions ( secondary cocoon ) like drugs ( practolol , propranolol ) , chronic ambulatory peritoneal dialysis , ventriculoperitoneal shunts , diseases such as sarcoidosis , sle , liver cirrhosis , uterine leiomyomas , endometriotic cysts or tumours of the ovary , etc .
( 14 ) we report the unusual case of a young female patient with repeated episodes of intestinal obstruction due to further encasement of the distal ileum within a separate membrane that was wholly within the outer covering cocoon a cocoon within a cocoon.
a 16 year old female patient presented to us repeatedly with episodes of small bowel obstruction that had previously responded to conservative management .
this time , she had a vague mass in the right iliac fossa in addition to her obstructive features .
although she responded to conservative management this time also , the mass did not disappear .
a computerised tomogram ( ct ) scan was done to assess the mass , which revealed a fixed obstruction at the terminal ileum along with dilatation of the small bowel above .
the whole of the stomach , small bowel and part of the ascending colon were encased by a thin membrane ( figure 1 ) .
thin membrane that was encasing the stomach , small intestine and part of the ascending colon ( black arrows ) once this membrane was opened up , it was found that the terminal ileum was jumbled up and encased within another thick membrane ( figure 2 ) that was separate from the outer covering .
jumbled up terminal ileum encased within another thick membrane ( black arrow ) the post operative period was uneventful .
the histopathology report of the two membranes was non - specific , and did not reveal any evidence of tuberculosis .
since it was first reported in 1907 , the abdominal cocoon still remains uncommon as a cause of intestinal obstruction . a search on pubmed revealed only about 92 articles on this topic ( abdominal cocoon ) to date .
as mentioned earlier , the cocoon can arise as a primary disease when there is no obvious etiology , or it can be secondary , in the setting of various factors as have been listed .
the primary form of the disease is much more common than the secondary form , and is seen usually in young females , especially from the tropical or subtropical countries .
although the etiology is not known , it has been hypothesised that it may arise as a response to subclinical primary viral peritonitis , gynecological infections , or retrograde menstruation ( 3 ) .
however , as the primary abdominal cocoon has been seen to occur in all ages , and even in males , casts some doubt on these factors solely being involved in the pathogenesis of the primary form of this unusual disease .
the offending condition is more obvious in the secondary form of abdominal cocoon , where bowel encapsulation occurs in the presence of a variety of factors listed previously .
it is uncommon for the diagnosis to be made with confidence preoperatively , since these patients present with non - specific signs and symptoms such as colicky abdominal pain , emesis and recurrent episodes of intestinal obstruction .
there are no specific radiological features of the disease that can give the diagnosis with certainty .
plain x - rays of the abdomen may reveal evidence of small bowel obstruction dilated bowel loops and air - fluid levels .
cauliflower appearance in which the intestinal loops are arranged in a concertina shape with a narrow base
. a ct scan may show dilated ileal loops towards the centre of the abdomen , or even , encasement by a membrane ( 5 ) .
however , it is often only at laparotomy ( 5 ) or during laparoscopy that the actual diagnosis is made , when part or whole of the small bowel is seen encased within a sac .
although the sac usually encases the small bowel , at times , it can extend to involve the colon , liver and even the stomach .
lysis of this sac is sufficient to relieve obstruction in most cases , but in a tubercular cocoon , it has been our experience that there are further adhesions between bowel loops that require adhesiolysis ( 3 ) .
however , in the absence of obvious evidence of tuberculosis within the abdomen , the diagnosis of tuberculosis as a cause of cocoon is only made with certainty following histological analysis .
the presentation reported here is unusual in that there was encasement of the terminal ileum within a sac , and this itself , along with rest of the small bowel , stomach and ascending colon was encased within a larger sac . despite an extensive search of available literature , we could not come across any similar case in which bowel being encased within a cocoon , that itself was encased within a larger cocoon , as reported here an abdominal cocoon within a cocoon ! | intestinal obstruction is a fairly common surgical emergency that usually occurs due to herniae , adhesions , or bands .
rarely , uncommon causes such as an abdominal cocoon are encountered , where part or all of the small intestine is encased within a thin membrane .
we report one such case of abdominal cocoon , in whom , further encasement of the distal ileum was seen within a separate membrane . | INTRODUCTION
CASE REPORT
DISCUSSION |
one of the flagship products of the human genome project ( hgp ) was a high - quality human reference assembly .
this assembly , coupled with advances in low - cost , high - throughput sequencing , has allowed us to address previously inaccessible questions about population diversity , genome structure , gene expression and regulation [ 2 - 5 ] .
it has become clear , however , that the original models used to represent the reference assembly inadequately represent our current understanding of genome architecture .
the first assembly models were designed for simple linear genome sequences , with little sequence variation and even less structural diversity .
the hgp constructed the reference assembly by collapsing sequences from over 50 individuals into a single consensus haplotype representation of each chromosome . employing a clone - based approach ,
the sequence of each clone represented a single haplotype from a given donor . at clone boundaries , however , haplotypes could switch abruptly , creating a mosaic structure .
this design introduced errors within regions of complex structural variation , when sequences unique to one haplotype prevented construction of clone overlaps .
the assembly therefore inadvertently included multiple haplotypes in series in some regions [ 7 - 9 ] .
the genome reference consortium ( grc ) began stewardship of the reference assembly in 2007 .
the grc proposed a new assembly model that formalized the inclusion of alternative sequence paths in regions with complex structural variation , and then released grch37 using this new model .
the release of grch37 also marked the deposition of the human reference assembly to an international nucleotide sequence database collaboration ( insdc ) database , providing stable , trackable sequence identifiers , in the form of accession and version numbers , for all sequences in the assembly .
the grc developed an assembly model that was incorporated into the national centre for biotechnology information ( ncbi ) and european nucleotide archive ( ena ) assembly database that provides a stable identifier for the collection of sequences and the relationship between these sequences that comprise an assembly .
fix patches that could be used to resolve mistakes in the reference sequence , as well as
the new assembly model presents significant advances to the genomics community , but , to realize those advances , we must address many technical challenges .
the new assembly model is neither haploid nor diploid - instead , it includes additional scaffold sequences , aligned to the chromosome assembly , that provide alternative sequence representations for regions of excess diversity .
widely used alignment programs , variant discovery and analysis tools , as well as most reporting formats , expect reads and features to have a single location in the reference assembly as they were developed using a haploid assembly model . many alignment and analysis tools penalize reads that align to more than one location under the assumption that the location of these reads can not be resolved owing to paralogous sequences in the genome
. these tools do not distinguish allelic duplication , added by the alternative loci , from paralogous duplication found in the genome , thus confounding repeat and mappability calculations , paired - end placements and downstream interpretation of alignments in regions with alternative loci . to determine the efforts needed to facilitate use of the full assembly , the grc organized a workshop in conjunction with the 2014 genome informatics meeting in cambridge , uk ( http://www.slideshare.net/genomeref ) .
participants identified challenges presented by the new assembly model and discussed ways forward that we describe here .
a graph structure is a natural way to represent a population - based genome assembly , with branches in the graph representing all variation found within the source sequences .
most assembly programs internally use a graph representation to build the assembly , but ultimately produce a flattened structure for use by downstream tools [ 12 - 14 ] . recently ,
formal proposals for representing a population - based reference graph have been described [ 15 - 17 ] .
the newly formed global alliance for genomics and health ( ga4gh ) is leading an effort to formalize data structures for graph - based reference assemblies , but it will likely take years to develop the infrastructure and analysis tools needed to support these new structures and see their widespread adoption across the biological and clinical research communities . the introduction of alternative loci into the assembly model provides a stepping - stone towards a full graph - based representation of a population - based reference genome .
the alternative loci provided by the grc are based on high - quality , finished sequence .
although it is not feasible to represent all known variation using the alternative locus scheme , this model does allow us to better represent regions with extreme levels of diversity .
alternative loci are not meant to represent all variation within a population , but rather provide an immediate solution for adding sequences missing from the chromosome assembly . in practice ,
alternative locus addition is limited by the availability of high - quality genomic sequence , and the grc has focused on representing sequence at the most diverse regions , such as the major histocompatibility complex ( mhc ) .
the representation of all population variation is better suited to a graph - based representation .
the high quality of the sequence at these locations provides robust data to test graph implementations . additionally ,
because both ncbi and ensembl have annotated these sequences , we can also begin to address how to annotate graph structures at these complex loci . while grch37 had only three regions containing nine alternative locus sequences
, grch38 has 178 regions containing 261 alternative locus sequences , collectively representing 3.6 mbp of novel sequence and over 150 genes not represented in the primary assembly ( table 1 ) .
the increased level of alternative sequence representation intensifies the urgency to develop new analysis methods to support inclusion of these sequences .
inclusion of all sequences in the reference assembly allows us to better analyze these regions with potentially modest updates to currently used tools and reporting structures .
although the addition of the alternative loci to current analysis pipelines might lead to only modest gains in analysis power on a genome - wide scale , some loci will see considerable improvement owing to the addition of significant amounts of sequence that can not be represented accurately in the chromosome assembly ( figure 1).table 1
examples of regions with alternative loci , sequences within these regions and genes unique to them
region name
sequence
chromosome
unique genes
apobecgl383583.222
apobec3a_b
mhcgl000250.26
hla - drb2
gl000251.2
hla - drb3
gl000252.2
hla - drb4
gl000253.2
hla - drb7
gl000254.2gl000255.2gl000256.2ki270758.1ccl5_tbc1d3ki270909.117
ccl3l1
ccl4l1
ccl3p1
cyp2d6kb663069.122
loc101929829 ( cyp2d6 pseudogene)lrc_kirki270938.1,19
lilra3
gl949747.2gl000209.2 ,
kir2ds1
gl949747.2ki270882.1,ki270887.1,ki270890.1,ki270916.1,ki270921.1trbki270803.17
trbv5 - 8
figure 1
histogram displaying unique sequence per alternative locus . while the vast majority of alternative loci contribute less than 50 kb of unique sequence , some contribute well over 100 kb of novel sequence .
examples of regions with alternative loci , sequences within these regions and genes unique to them
histogram displaying unique sequence per alternative locus .
while the vast majority of alternative loci contribute less than 50 kb of unique sequence , some contribute well over 100 kb of novel sequence .
omission of the novel sequence contained in the alternative loci can lead to off - target sequence alignments , and thus incorrect variant calls or other errors , when a sample containing the alternative allele is sequenced and aligned to only the primary assembly .
using reads simulated from the unique portion of the alternative loci , we found that approximately 75% of the reads had an off - target alignment when aligned to the primary assembly alone .
the 1000 genomes project also observed the detrimental effect of missing sequences and developed a
much of this decoy has now been incorporated into grch38 , and analysis of reads taken from 1000 genomes samples that previously mapped only to the decoy shows that approximately 70% of these now align to the full grch38 , with approximately 1% of these reads aligning only to the alternative loci ( figure 2).figure 2
( a ) alignment of decoy - specific reads to grch38 . to identify decoy - specific reads ,
the following read sets were used : /panfs / traces01/compress/1kg.p2/na19200.mapped.illumina.bwa.yri.low_coverage.20120522.8levels.csra and /panfs / traces01/compress/1kg.p2/na12878.mapped.illumina.bwa.ceu.low_coverage.20120522.8levels.csra . using srprism ( with parameters [ p ] ( force paired / unpaired search ) : false ; [ n ] ( maximum number of allowed errors ) : 6 ; [ m ] ( maximum allowed memory usage ) : 2048 . )
reads were extracted with mapq > 20 that uniquely aligned to sn : hs37d5 ( the decoy ) . as a control , these reads were aligned to a target set comprising the grch37 primary assembly unit ( gcf_000001305.13 ) , chr .
collectively , this target set is referred to as grch37pmd . to assess capture of the decoy sequence in the updated assembly
, the reads were aligned to a target set comprising the grch38 primary assembly ( gcf_000001305.14 ) and chr .
mt ( gcf_000006015.1 ) ( referred to as grch38pm ) or the full grch38 assembly ( gcf_000001405.26 ) .
a captured read was defined as one that aligned only to the decoy ( by srprism ) when using grch37pmd as the target set , and also aligned to grch38pm or full .
blue bars are assembly components ; gene annotations are shown in green . two components ( ac226006.2 and ac208587.4 , highlighted in red ) in this alt scaffold are fosmids from which decoy sequences were derived ( ac208587.4:750012511 , ac226006.2:55818770 , ac226006.2:2048321626 ) .
the decoy sequences represent variants from the chromosome . the alignment of the decoy fragments and grch38 chr .
11 to the alternative scaffold are shown as gray bars ( red tick , mismatch ; blue tick , deletion ; thin red line , insertion ) .
note that the decoy fragments align to regions that are missing from the reference chromosome .
an assembly component ( ac239832.2 , highlighted in red ) added to this region for grch38 is a fosmid from which decoy sequence was derived ( ac239832.3:660210993 , ac239832.3:2443427364 ) .
in this case , the decoy adds exonic sequence from muc2 that is missing from component ac139749.4 .
the alignments of the decoy fragments and nt_187681.1 to the alternative scaffold are shown as gray bars ( red tick , mismatch ; blue tick , deletion ; thin red line , insertion ) .
using srprism ( with parameters [ p ] ( force paired / unpaired search ) : false ; [ n ] ( maximum number of allowed errors ) : 6 ; [ m ] ( maximum allowed memory usage ) : 2048 . )
reads were extracted with mapq > 20 that uniquely aligned to sn : hs37d5 ( the decoy ) . as a control , these reads were aligned to a target set comprising the grch37 primary assembly unit ( gcf_000001305.13 ) , chr .
collectively , this target set is referred to as grch37pmd . to assess capture of the decoy sequence in the updated assembly
, the reads were aligned to a target set comprising the grch38 primary assembly ( gcf_000001305.14 ) and chr .
mt ( gcf_000006015.1 ) ( referred to as grch38pm ) or the full grch38 assembly ( gcf_000001405.26 ) .
a captured read was defined as one that aligned only to the decoy ( by srprism ) when using grch37pmd as the target set , and also aligned to grch38pm or full .
two components ( ac226006.2 and ac208587.4 , highlighted in red ) in this alt scaffold are fosmids from which decoy sequences were derived ( ac208587.4:750012511 , ac226006.2:55818770 , ac226006.2:2048321626 ) .
the decoy sequences represent variants from the chromosome . the alignment of the decoy fragments and grch38 chr .
11 to the alternative scaffold are shown as gray bars ( red tick , mismatch ; blue tick , deletion ; thin red line , insertion ) .
note that the decoy fragments align to regions that are missing from the reference chromosome .
an assembly component ( ac239832.2 , highlighted in red ) added to this region for grch38 is a fosmid from which decoy sequence was derived ( ac239832.3:660210993 , ac239832.3:2443427364 ) . in this case , the decoy adds exonic sequence from muc2 that is missing from component ac139749.4 .
the alignments of the decoy fragments and nt_187681.1 to the alternative scaffold are shown as gray bars ( red tick , mismatch ; blue tick , deletion ; thin red line , insertion ) .
we foresee many computational approaches that allow the inclusion of all assembly sequences in analysis pipelines . to better support exploration in this area , we propose some improvements to standard practices and data structures that will facilitate future development.enhancement of standard reporting formats ( such as bam / cram , vcf / bcf , gff3 ) so that they can accommodate features with multiple locations .
doing so while maintaining the allelic relationship between these features is crucial [ 21 - 24].adoption of standard sequence identifiers for sequence analysis and reporting . using shorthand identifiers ( for example ,
chr1 or 1 ) to indicate the sequence is imprecise and also ignores the presence of other sequences in the assembly . in many cases , other top - level sequences , such as unlocalized scaffolds , patches and alternative loci ,
these sequences are independent of the chromosome assembly coordinate system and have their own coordinate space .
alternative loci are related to the chromosome coordinates through alignment to the chromosome assembly . developing a structure that treats all top - level sequences as first - class citizens during analysis is an important step towards adopting use of the full assembly in analysis pipelines.curation of multiple sequence alignments of the alternative loci to each other and the primary path . currently , pairwise alignments of the alternative loci to the chromosome assembly are available to provide the allelic relationship between the alternative locus and the chromosome
. however , these pairwise alignments do not allow for the comparison of alternative loci in a given region to each other .
the relationship of the allelic sequences within a region helps define the assembly structure , and the community should work from a single set of alignments .
enhancement of standard reporting formats ( such as bam / cram , vcf / bcf , gff3 ) so that they can accommodate features with multiple locations .
doing so while maintaining the allelic relationship between these features is crucial [ 21 - 24 ] .
chr1 or 1 ) to indicate the sequence is imprecise and also ignores the presence of other sequences in the assembly . in many cases , other top - level sequences , such as unlocalized scaffolds , patches and alternative loci ,
these sequences are independent of the chromosome assembly coordinate system and have their own coordinate space .
developing a structure that treats all top - level sequences as first - class citizens during analysis is an important step towards adopting use of the full assembly in analysis pipelines .
curation of multiple sequence alignments of the alternative loci to each other and the primary path .
currently , pairwise alignments of the alternative loci to the chromosome assembly are available to provide the allelic relationship between the alternative locus and the chromosome
. however , these pairwise alignments do not allow for the comparison of alternative loci in a given region to each other .
the relationship of the allelic sequences within a region helps define the assembly structure , and the community should work from a single set of alignments .
recently , the grc has released a track hub that allows for the distribution of grc data using standard track names and content ( http://ngs.sanger.ac.uk/production/grit/track_hub/hub.txt ) .
additionally , the grc has created a github page to track development of tools and resources that facilitate use of the full assembly ( https://github.com/genomeref/softwaredevtracking ) .
as we gain understanding of biological systems , we must update the models we use to represent these data .
this can be difficult when the model supports common infrastructure and analysis tools used by a large swath of the scientific community .
however , this growth is crucial in order to move the scientific community forward . while adoption of this new model will take substantial effort
, doing so is an important step for the human genetics and broader genomics communities .
we now have an opportunity and imperative to revisit old assumptions and conventions to develop a more robust analysis framework .
the use of all sequences included in the reference will allow for improved genomic analyses and understanding of genomic architecture .
additionally , this new assembly model allows us to take a small step towards the realization of a graph - based assembly representation .
the evolution of the assembly model allows us to improve our understanding of genomic architecture and provides a framework for boosting our understanding of how this architecture impacts human development and disease . | the human genome reference assembly is crucial for aligning and analyzing sequence data , and for genome annotation , among other roles .
however , the models and analysis assumptions that underlie the current assembly need revising to fully represent human sequence diversity .
improved analysis tools and updated data reporting formats are also required . | Background
Towards the graph of human variation
Concluding remarks |
myofibroblasts were first described in healing skin wounds , where it was hypothesized that they were responsible for the phenomenon of wound contraction.1 since then , cells morphologically similar to myofibroblasts have been described in many tissues , predominantly in pathological states where their sustained presence is generally a marker of fibrosis and scarring.2 early studies identified myofibroblasts on the basis of their ultrastructural morphology , with prominent microfilament bundles in their cytoplasm distinguishing them from
myofibroblasts also possessed fibronexus junctions between cells and the surrounding extracellular matrix ( ecm ) , thus in some ways appearing to share some of the morphological characteristics of smooth muscle ( sm ) cells.3 many tissues and pathologies have been described in which myofibroblasts have been identified , including hypertrophic and keloid scars in the skin , fibrotic liver as seen in liver cirrhosis and other liver pathologies , renal fibrosis , and idiopathic pulmonary fibrosis.4 more recently , cells with phenotypic features of myofibroblasts have also been found in and around a number of epithelial tumors , where they have been termed cancer - associated fibroblasts or stromal myofibroblasts.57 the role of myofibroblasts in driving fibrotic diseases , and the recent finding that cancer - associated myofibroblasts likely influence tumor growth and correlate with poor clinical prognosis , has increased our interest in their cellular origins , their regulation , and their role in repair and disease.8 after early studies that defined myofibroblasts on the basis of their ultrastructural morphology , later research using antibodies and immunohistochemistry resulted in myofibroblasts and their microenvironment being more clearly defined.9 it is now accepted that myofibroblasts go through a precursor stage of expressing large stress fibers that are not seen in quiescent fibroblasts , prominent bundles of microfilaments that permit some contraction and pre - stressing and remodeling of the surrounding ecm.10 later , fully differentiated myofibroblasts show expression of the usually sm - specific cytoskeletal protein , -sm actin , which is now often used to define the myofibroblast phenotype.9,11 the presence of a splice variant form of fibronectin ( ed - a fibronectin ) in the microenvironment adjacent to the myofibroblast is also a defining feature and appears to be required for their differentiation.12 de novo expression of osteoblast ( ob ) cadherin has also been reported to be found on the surface of differentiated myofibroblasts , and is not seen on -sm actin - negative fibroblasts.13 the other defining feature of myofibroblasts is that they fail to express the full repertoire of sm cell markers , allowing myofibroblasts to be distinguished from sm cells .
specifically , myofibroblasts in most cases are negative for sm cell markers such as sm myosin heavy chain,14 n - caldesmon,15 and smoothelin.16 desmin has also been used as a negative marker of myofibroblasts . generally , sm cells express desmin and vimentin as well as sm myosin , while myofibroblasts express only vimentin .
however , some situations have been reported in the literature where myofibroblasts in some pathologies have been found to be desmin positive.17 distinguishing myofibroblasts from pericytes is perhaps more problematic since pericytes can closely resemble myofibroblasts in being -sm actin positive , vimentin and desmin positive , but sm myosin negative.15,18 indeed , pericytes may in some cases be a source of myofibroblasts in some conditions , including wound repair , where myofibroblasts may represent a pericyte that has lost some phenotypic features such as desmin expression.19 similarly , sm cells from the media of an injured blood vessel may lose late differentiation markers such as desmin , smoothelin , and sm myosin and acquire a myofibroblast phenotype.20
lastly , myofibroblasts show both fibronexus junctions with other cells and specialized junctional complexes with the ecm ; these large mature focal adhesions allow them to make strong attachments , contract and remodel the ecm , and provide a means of transducing mechanical force in the tissue.21,22 the contractile nature of myofibroblasts has some similarities to sm cells , despite the differences in expression of cytoskeletal features .
for example , the calcium signaling in myofibroblasts appears to be similar to that in sm cells , and the arrangement of cells into something resembling that of sm cells in tissues with single - unit sm is also similar , that is , with cells having junctional complexes and connections ( including gap junctions ) that allow the spread of contraction signals through the tissue .
contraction of myofibroblasts seems to be possible through ca - dependent mechanisms that are similar to those present in sm cells , with increased free ca regulating phosphorylation of myosin light chain .
this may explain the rapid contractile responses of myofibroblasts in vitro to agonists such as angiotensin ii or endothelin .
slower and more sustained contraction , which is perhaps more typical of what occurs during slow retractile contraction of connective tissue in granulation tissue , involves activity of the guanosine triphosphate ( gtp)-ase rhoa and activation of its downstream target rho - associated kinase ( rock ) .
immediately after wounding , the healing process commences , leading to ( partial ) restoration of injured tissue . wound healing proceeds in three interrelated dynamic phases that temporally overlap ( figure 1 ) . based on morphological changes over the course of the healing process
, these phases are defined as the inflammatory phase , the proliferative phase ( the development of granulation tissue ) , and the regeneration phase , including maturation , scar formation , and re - epithelialization.24 the inflammatory phase begins with damage of capillaries , triggering the formation of a blood clot consisting of fibrin and fibronectin .
this provisional matrix fills in the lesion and allows a variety of recruited cells to migrate into the lesion .
platelets present in the blood clot release multiple chemokines , which participate in the recruitment of inflammatory cells , neutrophils , and macrophages , but also in chemotaxis and recruitment of fibroblasts and endothelial cells .
angiogenesis , which is critical for the wound healing process , allows new capillaries to deliver nutrients to the wound , and contributes to the proliferation of fibroblasts .
initially the wound is hypoxic due to the loss of vascular perfusion , but with the development of a new capillary network , vascular perfusion is restored .
regulating wound angiogenesis in itself may represent a means for improving healing in some cases , particularly where delayed or defective angiogenesis is implicated in healing impairment.25 in the granulation tissue , fibroblasts are activated and acquire -sm actin expression and become myofibroblasts .
these myofibroblastic cells synthesize and deposit the ecm components that eventually replace the provisional matrix ( figure 2 ) .
these cells exhibit contractile properties , due to the expression of -sm actin in microfilament bundles or stress fibers , playing a major role in the contraction and maturation of the granulation tissue.26 presently , it is accepted that the myofibroblastic modulation of fibroblastic cells begins with the appearance of the protomyofibroblast , whose stress fibers contain only - and -cytoplasmic actins .
protomyofibroblasts generally evolve into differentiated myofibroblasts , the most common variant of this cell , with stress fibers containing -sm actin ( for review , see tomasek et al27 ) .
myofibroblasts can , depending on the experimental or clinical situation , express other sm - related contractile proteins , such as sm myosin heavy chains or desmin ; however , the presence of -sm actin represents the most reliable marker of the myofibroblastic phenotype.27 the third phase of healing , scar formation , involves a progressive remodeling of the granulation tissue . during this remodeling process
, proteolytic enzymes , essentially matrix metalloproteinases ( mmps ) and their inhibitors ( tissue inhibitor of metalloproteinases [ timps ] ) play a major role.28 the synthesis of ecm is not totally stopped , but considerably reduced , and the synthesized components are modified as the matrix is remodeled .
progressively , collagen type iii , the major component of the granulation tissue , is replaced by collagen type i , which is the main structural component of the dermis .
lastly , elastin , which contributes to skin elasticity and is absent in the granulation tissue , also reappears . in the resolution phase of healing , the cell number is dramatically reduced by apoptosis of both vascular cells and myofibroblasts.29 to date , it is not known whether myofibroblasts can reacquire a quiescent phenotype , that is , return to a normal dermal fibroblast phenotype with no expression of -sm actin ( figure 2 ) .
it is generally accepted that the major source of myofibroblasts are local connective tissue fibroblasts that are recruited into the wound.30 dermal fibroblasts located at the edges of the wound can acquire a myofibroblastic phenotype and participate in tissue repair.31 however , important heterogeneity in fibroblastic cell subpopulations has also been observed .
these subpopulations reside in different locations within the skin and have specific activation and deactivation properties .
at least three subpopulations have been identified in the dermis : superficial ( or papillary ) fibroblasts ( papillary dermis is around 300400 m deep and is arranged as a ridge - like structure ) , reticular fibroblasts , which reside in the deep dermis ( made of thick collagen and elastin fibers arranged parallel to the surface of the skin ) , and fibroblasts associated with hair follicles .
these cell subpopulations can be isolated and exhibit , depending of the nature and age of the original skin , distinct phenotypic differences when cultured separately.32,33 recently , the involvement in tissue repair of local mesenchymal stem cells has been increasingly raised .
these progenitor cells have been described in the dermal sheath that surrounds the outside of the hair follicle facing the epithelial stem cells .
they are involved in the regeneration of the dermal papilla and can also became wound healing ( myo)fibroblasts after a lesion or injury.34,35 recent data have also implicated circulating cells , dubbed fibrocytes , in the tissue repair process .
fibrocytes enter injured skin together with inflammatory cells and may then acquire a myofibroblastic phenotype.36 in postburn scars , fibrocytes are recruited to the site of the lesion where they stimulate the local inflammatory response and produce ecm proteins , thus contributing to hypertrophic scar formation.37 another type of circulating cell originating from bone marrow has also been suggested to play a role in tissue repair .
mesenchymal stem cells are bone marrow - derived non - hematopoietic precursor cells38 that contribute to the maintenance and regeneration of connective tissues through engraftment.39 indeed , they have the capacity to seed into several organs and to differentiate into wound - healing myofibroblasts .
this engraftment in injured organs is regulated by the severity of the damage.40 finally , differentiated ( or malignant ) epithelial and endothelial cells can undergo a phenotypic conversion that gives rise to matrix - producing fibroblasts and myofibroblasts ( through epithelial- and endothelial - to - mesenchymal transition processes).41 this mechanism is increasingly recognized as an integral part of tissue fibrogenesis after injury , but seems to play a limited role during normal tissue repair .
overall , mesenchymal stem cells , fibrocytes , bone marrow - derived cells , and cells derived from epithelial - and endothelial - to - mesenchymal transition processes may represent alternative sources of myofibroblasts when local fibroblasts are not sufficient to carry out tissue repair and remodeling .
myofibroblasts are implicated in many fibrotic and scarring diseases , where they carry out the important process after initial injury of providing mechanical support and integrity to the tissue . in normal physiological conditions ,
they are then lost via apoptosis , generally when the tissue integrity has been sufficiently restored to be mechanically coherent.9,29 thus , in normal physiological situations like skin wound healing , myofibroblasts disappear in a prominent wave of apoptosis , leaving a markedly less cellular scar .
however , it is now assumed that , in many fibrotic and scarring conditions , as well as in the stromal response to tumors , myofibroblasts fail to undergo cell death , persist , and thus in turn lead to ongoing pathology and scarring ( figure 3 ) .
an example of reduced or inhibited apoptosis leading to scarring is in a model of hypertrophic scarring , where mechanical loading increases survival of myofibroblasts and was found to lead to greater scar formation.42,43 a better understanding of the control and signaling that governs apoptosis ( or autophagy ) in myofibroblasts may lead to more targeted approaches to combatting fibrosis and scarring .
it has been demonstrated that elevated nicotinamide adenine dinucleotide phosphate ( nadph ) oxidase 4-derived hydrogen peroxide , supported by concomitant decreases in nitric oxide signaling and reactive oxygen species scavengers , are central factors in the molecular pathogenesis of fibrosis.44 redox signaling could therefore represent an interesting target to restore the physiological fibroblast myofibroblast ratio .
apoptosis in myofibroblasts is thought to be regulated by a reduction in the local growth factors that drive and sustain myofibroblast differentiation . in particular , local concentrations of transforming growth factor ( tgf)-1 and endothelin-1 play a role in stimulating myofibroblast survival via protein kinase b ( akt ) activation.45 however
, changes in mechanical signaling such as unloading of mechanical force likely also plays a role ( discussed below ) .
the importance of myofibroblasts in causing fibrosis in internal organs and the skin ( hypertrophic scars ) , and the role that persistence of stromal myofibroblasts appear to play in tumor growth and spread , makes the ( down)regulation of myofibroblasts and the potential regulation of myofibroblast disappearance through apoptosis of increasing interest ( figure 4 ) ( for review , see hinz and gabbiani46 ) .
mechanical signals have been shown to play a role in myofibroblast differentiation as the ecm that surrounds the fibroblasts in damaged tissue changes its composition and its stiffness as tissue repair proceeds.47 the early ecm present in damaged tissue , or provisional matrix , is rich in fibrin and has been estimated to be very compliant .
fibroblasts cultured in compliant ecm such as soft three - dimensional ( 3d ) collagen gels , show little development of stress fibers .
these fibroblasts then form only small adhesions with the ecm.48,49 fibroblasts grown in stiffer collagen matrices have been shown to form stress fibers and mature focal adhesions , though they are still negative for the myofibroblast marker -sm actin .
lastly , the stiff matrix found either in 3d cultures using stiff ( higher concentration ) collagen matrix or in vivo in granulation tissue and fibrotic tissues is able to induce full myofibroblast differentiation in concert with growth factor stimulation from tgf-1.22 the contractile nature of myofibroblasts itself leads to an increase in stiffness and mechanical stress of the ecm as healing progresses , leading to a positive - feedback loop where increased stress signals myofibroblast differentiation and also increases myofibroblast survival.42 for this reason , mechanical feedback is considered to be important in driving pathological conditions such as contractures post - injury .
the role of mechanical stress in stimulating myofibroblast activity has also been shown in experiments where dermal wounds in mice are mechanically stressed by stretching or splinting the wound , where increased myofibroblast activity results in increased scar formation , to some extent mimicking hypertrophic scarring that is seen in humans.42 in cancer biology , matrix stiffness can be used as a diagnostic indicator of the risk of malignancy and appears to correlate with increased invasiveness of tumors , for example in breast cancer where density of tissue on mammography correlates strongly with the risk of cancer formation .
recent studies have suggested this may be due to increased cell proliferation of epithelial and mesenchymal cells on stiffer matrices .
conversely , releasing mechanical stress or reducing stiffness has been shown to induce both apoptosis and a reduction in -sm actin expression and contractility in myofibroblasts.50,51 mechanical signaling and stress modulate myofibroblast differentiation via a number of pathways and mechanisms .
stress may directly activate transcription of the -sm actin gene , since application of force across integrin binding sites has been shown to up - regulate -sm actin promoter activity.52 as mentioned above , mechanical force alone is not generally sufficient to induce myofibroblast differentiation and other factors are needed to act in concert , specifically tgf-1 .
mechanical signaling and tgf-1 stimulation also increase collagen gene expression by fibroblasts , emphasizing the role these factors play in stimulating a pro - fibrotic phenotype as is shown by activated myofibroblasts .
tgf-1 also favors deposition of ecm proteins over degradation by up - regulating timps while decreasing expression of the mmps themselves.53 stimulation of myofibroblasts by tgf-1 itself is affected by mechanical forces within the damaged or fibrotic tissue .
tgf-1 released from a variety of inflammatory cells and platelets in the microenvironment of damaged or fibrotic tissue is in a latent form .
indeed , myofibroblasts themselves release latent tgf-1 complexed with latency - associated peptide ( lap ) .
together with a binding protein , tgf-1 is bound to ecm proteins , providing a reservoir of latent tgf-1 that can be activated as healing and scar formation progress.54,55 myofibroblasts express integrins that can bind to the lap , and mechanical stress applied to the integrins , either by mechanical stress on the matrix and/or via myofibroblast contraction , can effectively activate tgf-1 without cleaving the lap and allow its binding to cell membrane receptors.51 thus , both increased mechanical stress and contraction can further increase myofibroblast contractile and matrix synthetic activity .
this mode of activation provides another possible pathway for regulating myofibroblast activity by blocking integrin binding to latent tgf-1 , for example by blocking the integrin involved in latent tgf-1 activation , v5.56 inhibition of other integrin - binding sites has also been shown to inhibit myofibroblast development , including blocking of integrins 31,57 111,58 v5,59 or 1.60
tissue oxygenation or hypoxia may play a role in both normal healing and pathological situations . in normal wound healing ,
staining for the hypoxia - induced transcription factor , hypoxia inducible factor ( hif)-1 shows both areas of the early granulation tissue and the overlying migrating keratinocytes to be hypoxic . during normal healing , this hypoxia
hypoxia signaling can induce a number of growth factors that are beneficial to the healing process , prominent amongst them being vascular endothelial growth factor ( vegf ) and , thus , acute hypoxia likely plays a beneficial role in healing .
however , the same may not be true for chronic hypoxia and chronic hypoxia signaling .
hypoxia has been reported to reduce myofibroblast activation and reduce collagen synthesis and -sm actin expression.61 in vivo studies using hif-1-deficient mice showed that reducing hif-1 availability during healing resulted in reduced collagen synthesis and delayed myofibroblast differentiation , suggesting that , overall , in vivo acute hypoxia during healing was normally compensated by induction of genes that allow tissue to adapt to transient hypoxia , such as vegf.62 in fact , fibroblasts that show reduced hif-1 expression during hypoxia show inhibited migration and collagen synthesis in vitro .
it is possible that , in some organs where there is pathological fibrosis and scarring , hypoxia and hif signaling , possibly during more chronic hypoxic states , actually drives fibrosis , which has been suggested in the case of renal fibrosis . in some cells at least , there is cross talk between hypoxia signaling and tgf- signaling that may exacerbate matrix synthesis and thus fibrosis.63,64
anti - fibrotic and anti - scarring therapies have proven to be a difficult and elusive area for research , with relatively few advances until quite recently . as the growth factor
tgf- is central to many of the mechanisms of pathological scarring and fibrosis , it has been the target of some therapeutic strategies .
some positive results have been reported with the drug pirfenidone , particularly in lung fibrosis , where the drug lowered tgf- expression and both tissue and lavage fluid levels of the protein.65 interfering with activation of latent tgf- is another potential target for anti - scarring therapies , and the role of integrin binding in tgf- activation makes integrin - blocking antibodies a potential therapy for lowering tgf- activation and thus downstream signaling.66,67 specific inhibitors of tgf- signaling have also been suggested as possible treatments for scarring and fibrosis .
tgf- exerts its pro - fibrotic effects through transcription factor signaling smad3 , and selective inhibition of smad3 phosphorylation and inhibition of smad3 interaction with smad4 has been shown to reduce fibroblast activation to the myofibroblast phenotype and also reduce ecm synthetic activity of the cells.68 other molecular targets include tyrosine kinases , and the drug imatinib mesylate has been reported to be anti - fibrotic through inhibiting downstream molecules that are required for the tgf- response while having an additional anti - fibrotic role by also inhibiting platelet - derived growth factor signaling.69 interestingly , hmg - coa reductase inhibitors such as statins have been shown to have anti - fibrotic effects , likely through inhibition of rock.70 the widespread use of , and low rate of side effects associated with , these drugs may make them promising as anti - fibrotic therapies in the future .
since their first description in the early 1970s , our knowledge about myofibroblast biology has increased greatly , and our interest in the biology of myofibroblasts has also increased , as this cell has been implicated in many pathological situations in addition to their role in normal wound repair . despite major advances in our understanding of the origins of myofibroblasts and the factors that regulate their differentiation and activity , it remains a challenge and a major goal of researchers to find ways in which to regulate their activity to improve healing and scarring in the clinic .
it is densely innervated by different sensory nerve fiber subtypes that react to tissue injury , temperature variation , and tactile stimuli ( figure 5 ) .
cutaneous sensory nerve fibers are endings of dorsal root ganglia ( or spinal ganglia ) neurons that carry signals from sensory organs toward the appropriate integration center of the brain or of the spinal cord .
several clinical observations indicate that damage to the peripheral nervous system influences wound healing , sometimes resulting in chronic wounds within the affected area .
patients with cutaneous sensory defects due to spinal cord injury or diabetic neuropathy have an increased risk of developing ulcers that fail to heal . in addition , in aged patients , cutaneous repair processes are less efficient and this could be partly due to a deterioration of the peripheral nervous system at the skin level .
interestingly , factors that are required for sustaining peripheral nerves , the neurotrophin network , have also been shown to have direct effects on dermal fibroblasts in regulating ecm secretion , fibroblast differentiation , and tensile strength via effects on myofibroblasts.71 understanding the role of innervation during wound healing and myofibroblastic differentiation therefore represents an interesting domain .
in addition , cutaneous innervation is certainly necessary to provide good hemostasis and to maintain the mechanical and cosmetic properties of the skin.72 in conclusion , the recent advances made in understanding control of differentiation , proliferation , and survival of myofibroblasts will hopefully lead to new therapeutic approaches to limit scarring and improve healing in the not - too - distant future.73 | ( myo)fibroblasts are key players for maintaining skin homeostasis and for orchestrating physiological tissue repair .
( myo)fibroblasts are embedded in a sophisticated extracellular matrix ( ecm ) that they secrete , and a complex and interactive dialogue exists between ( myo)fibroblasts and their microenvironment .
in addition to the secretion of the ecm , ( myo)fibroblasts , by secreting matrix metalloproteinases and tissue inhibitors of metalloproteinases , are able to remodel this ecm .
( myo)fibroblasts and their microenvironment form an evolving network during tissue repair , with reciprocal actions leading to cell differentiation , proliferation , quiescence , or apoptosis , and actions on growth factor bioavailability by binding , sequestration , and activation .
in addition , the ( myo)fibroblast phenotype is regulated by mechanical stresses to which they are subjected and thus by mechanical signaling . in pathological situations ( excessive scarring or fibrosis ) , or during aging , this dialogue between the ( myo)fibroblasts and their microenvironment may be altered or disrupted , leading to repair defects or to injuries with damaged and/or cosmetic skin alterations such as wrinkle development .
the intimate dialogue between the ( myo)fibroblasts and their microenvironment therefore represents a fascinating domain that must be better understood in order not only to characterize new therapeutic targets and drugs able to prevent or treat pathological developments but also to interfere with skin alterations observed during normal aging or premature aging induced by a deleterious environment . | Introduction to the myofibroblastic phenotype
Role in wound healing
Origin of wound myofibroblasts
Role of myofibroblasts in diseases (excessive scarring/fibrosis)
Regulation of myofibroblasts by mechanical forces
Hypoxia
Therapies
Conclusion |
liczba prac porwnujcych klasyczne badanie cystouretrografii mikcyjnej i badanie ultrasonograficzne z uyciem rodkw kontrastujcych drugiej generacji jest jednak niewielka .
dotd nie opublikowano pracy , ktra porwnaaby jednoczasowo obie metody w diagnostyce odpyww pcherzowo - moczowodowych .
prezentowana praca ma na celu ocen zgodnoci midzy badaniem ultrasonograficznym z uyciem rodkw kontrastujcych drugiej generacji i badaniem cystouretrografii mikcyjnej .
w okresie od kwietnia 2013 do maja 2014 roku jednoczasowe badanie ultrasonograficzne z uyciem rodkw kontrastujcych drugiej generacji i cystouretrografii mikcyjnej wykonano u 83 dzieci ( 37 dziewczynek i 46 chopcw , rednia wieku 3,5 roku , zakres wieku od 1 miesica do 17,5 roku ) .
w badaniu wykazano podobn czuo obu metod diagnostycznych w diagnostyce odpyww pcherzowo - moczowodowych , na poziomie 88% , adna z metod nie osigna wyniku 100% .
ujemna warto predykcyjna dla obu metod wyniosa 97% i nie wykazano adnej istotnej rnicy pomidzy obiema metodami w zakresie diagnostyki odpyww pcherzowo - moczowodowych .
naley jednak pamita o moliwych ograniczeniach badania ultrasonograficznego z uyciem rodkw kontrastujcych drugiej generacji w diagnostyce fazy mikcyjnej u niespokojnych , paczcych w trakcie badania dzieci .
vesicoureteral reflux ( vur ) is one of the most important contributors to kidney scarring , chronic kidney disease and end - stage renal disease , with the prevalence of 3050% in pediatric and 20% in adult population . over the years
, the number of indications for voiding cystourethrography ( vcug ) has decreased as a result of its potential radiation - related side effects . with the introduction of low - dose pulsed fluoroscopy ionizing radiation
a promising alternative method for vcug , lacking ionizing radiation , was introduced , namely contrast enhanced voiding urosonography ( ce - vus ) . while the majority of previous studies used first - generation ultrasound contrast agents ( ucas ) , currently only second - generation ucas are available for clinical use .
the two generations of ucas significantly differ regarding their physical properties influencing the examination technique and results .
there is a limited number of publications that support the potential role of second - generation contrast agents in diagnosis and management of vur in children .
previous studies have proved that ce - vus is a highly sensitive and radiation - free diagnostic tool for vur imaging in children .
nonetheless the major limitation of all previous studies was a lack of simultaneous performance of both procedures , influencing the final results .
in contrast , our prospective study is the first to compare the sensitivity and feasibility of both methods , vcug and ce - vus , in addition to the simultaneous use of second - generation ucas .
to assess the sensitivity of ce - vus with second generation ucas in the diagnosis of vur in children . to evaluate agreement between vcug and ce - vus in diagnosing vur in children
from april 2013 to may 2014 , 83 children ( 37 female and 46 male ) , mean age 3.5 years , age range from 1 month to 17.5 years underwent prospective simultaneous assessment with ce - vus and vcug .
parents / legal guardians were informed about the study protocol and methodology prior to the examination . informed written consent
the inclusion criteria for reflux examination included recurrent urinary tract infections , sonographically diagnosed dilatation of the urinary collecting system , suspicion of reflux nephropathy , follow - up of vur and neurogenic bladder .
the patients were catheterized transurethrally under aseptic conditions with 6f10f feeding tubes lubricated with lidocaine hydrochloride anesthetic gel ( xylocaine ) .
a plastic bottle containing 250 ml of saline solution ( sodium chloride 0.9% ) pre - warmed to 32c , 0.5 ml of sono vue and 30 ml of visipaque ( iodixanolum , ge healthcare a.s , ireland ) was connected through a drip system to the catheter , and placed about 80 cm above the examination table .
the solution of contrast agents for clinical use was prepared shortly before the exam under aseptic conditions .
a pre - warmed plastic bottle containing 0.9% saline was filled with iodine contrast agent , followed by 0.5 ml of sono - vue .
the mixture was gently shaken several times , until it appeared homogenous . before the examination , the solution of saline and both contrast media was examined in vitro to check for the presence of any unwanted particle formation .
immediately after reconstitution , 5 ml of solution ( prepared in the same manner as for the clinical examination ) were added to five petri dishes . from each petri dish
one test sample was taken after 1min , 2 min , 3 min , 5 min , and 10 min , and viewed under microscope with standard magnification , with no precipitates seen .
the total volume of the bladder was calculated using koff s formula : volume in milliliters = ( age in years + 2 ) 30 . filling of the bladder was performed until the child had to void , or the calculated volume was reached , or the dripping speed of infusion slowed down due to back pressure .
the child was in the supine position , with both kidneys , the bladder , and the lower ureter scanned alternately during continued filling and voiding , using the contrast enhanced ultrasound option .
vcug was performed without continuous real - time fluoroscopic monitoring , so the person conducting ce - vus was blind to vcug results .
spot films were taken after filling the bladder ( visible on ultrasound ) , and during the voiding phase .
the urethra was assessed in most cases using x - ray in an attempt to avoid additional catheterization for the ce - vus examination , thus simultaneous assessment was technically impossible .
the diagnosis of reflux was based on the appearance of high echogenicity microbubbles in the ureter or pelvicalyceal system .
vcug reflux grading was based on international system of radiographic grading of vur . in ce - vus reflux grading system
all subjects underwent a baseline gray - scale us examination of the urinary tract in the supine position .
all us examinations were performed using voluson e8 ( ge medical systems , milwaukee , wi , usa ) ; 48 mhz convex and 712 linear probes or aloka 6 ( aloka , hitachi - aloka medical , ltd , japan ) ; 5.08.0 mhz convex and 8.012.0 mhz linear probes .
since there is no gold standard in the diagnosis of vur ( false negatives results could occur ) , final diagnosis ( fd ) was established as the reference method . in particular , the patient was considered as having vesicoureteral reflux when the presence of vur was detected by either of the compared methods ( ce - vus or vcug ) .
this approach seems to be correct , since both methods do not provide false positives results ( type i error ) .
therefore , the analysis was reduced to calculations of sensitivity , as specificity would result as 100% .
statistical analysis was performed with statistica software ( version 10.0 ; statsoft , inc . ;
the results of recognition by vcug , ce - vus and fd were presented by summary frequency tables .
agreement between vcug and ce - vus methods was determined by the value of cohen s kappa coefficient .
test of independence between the side of the kidney and the final diagnosis of vur was implemented with the use of yates chi - square statistics .
sensitivity was set for vcug and ce - vus separately for left and right kidney , and enhanced with negative predictive values .
no complications and side - effects of simultaneous intravesical application of the two contrast agents were observed .
the diagnosis of vur was established in 33/166 uretero - renal units ( 20% ) , in 16 cases to the right kidney and in 17 to the left kidney ( tab .
1 ) . there was no significant difference between the sides of renal reflux ( p>0.05 ) ( tab .
frequency distribution of the final imaging diagnosis 0 vesicoureteral reflux ( vur ) negative , 1 vur positive independence test for the left kidney vs right kidney based on the final diagnosis of vesicoureteral reflux df
degrees of freedom grading of vesicoureteral reflux diagnosed uru uretero - renal units vur was not detected by ce - vus , but identified by vcug in 4 uretero - renal units , ( 3 of them were grade 2 and 1 grade 1 ) .
4 uretero - renal units were diagnosed only in ce - vus ( 2 of them were grade 2 and 2 grade 1 ) ( tab .
the distribution of the results of each method compared with the final diagnosis ( fd ) is described in table 5 and table 6 .
frequency distribution of the final diagnosis of both methods : voiding cystourethrography ( vcug ) and ce - vus 0 vesicoureteral reflux ( vur ) negative ; 1 vur positive summary frequency distribution of voiding cystourethrography ( vcug ) results vs. final diagnosis 0 vesicoureteral reflux ( vur ) negative ; 1 vur positive summary frequency distribution of contrast - enhanced voiding urosonography ( ce - vus ) results vs. final diagnosis 0 vesicoureteral reflux ( vur ) negative ; 1 vur positive the agreement between ce - vus and vcug in the diagnosis or exclusion of vur reached more than 95% ( tab .
7 ) , and using landis and koch interpretation of cohen s kappa coefficient ( 0.83 ) it is nearly perfect .
agreement of voiding cystourethrography ( vcug ) and contrast - enhanced voiding urosonography ( ce - vus ) in establishing final diagnosis assuming that vur detected by both methods was a true - positive result , and no reflux found by either method was representative of a true negative , the sensitivity of ce - vus and vcug for detection of vur amounted to 87.9% for each method .
the negative predictive value of ce - vus and vcug was 97% , and there was no difference between both methods .
distribution of sensitivity and negative predictive value of voiding cystourethrography ( vcug ) and contrast - enhanced voiding urosonography ( ce - vus ) rk right kidney , lk left kidney , npv negative predictive value in two cases with negative vcug results diagnosis with ce - vus was impossible due to the damaging of microbubbles of the contrast agent in constantly crying children .
there were technical difficulties to correctly perform vcug and ce - vus in 5 children , mainly due to problems with achieving the voiding phase .
in one case , voiding could be achieved only in the upright position , while in 4 cases spot films were not technically excellent , and not fully diagnostic during ce - vus / vcug .
ce - vus , introduced in the early 1990s was originally thought to be a promising alternative method for classical vcug . the short half - life and quite fast contrast destruction substantially limited the use of this method .
however , the methodology of ce - vus has changed over the last decade , especially due to the contrast agents now used for examination .
indeed , the second - generation ucas have been recently introduced for common clinical use , replacing the older contrast agents including levovist ( bayer - schering pharma , berlin , germany ) which was commonly used in ce - vus , but has been recently withdrawn from the market by the producer . in comparison to the second generation ucas , the first uca generation was not durable , and the results were highly dependent on the agent s concentration level in the bladder .
there are two major limitations of the use of second - generation ucas in pediatric population , namely off - label use in the population , and the limited number of studies evaluating the sensitivity and specificity of this method . according to the european society of pediatric radiology ( espr ) , standard vcug should be performed under fluoroscopic guidance enhanced with several spot films . the examination results in effective radiation dosage of around 0.50.8 msv . in our study , we abandoned fluoroscopy , as we had continuous observation of the urinary tract in ce - vus .
our study found no significant difference in sensitivity between ce - vus and vcug , suggesting that both methods can be alternatively used with some reservations ( fig . 1 ,
a. picture demonstrating the collecting system of the right kidney before the administration of the contrast solution into the urinary bladder .
b. reflux of the contrast agent to both collecting systems of duplicated right kidney in ce - us exam ( white arrows ) . c. the same patient during vcug examination ( black arrows ) a. picture demonstrating the collecting system of the right kidney before the administration of the contrast solution into the urinary bladder .
b. high grade reflux to the collecting systems of the right kidney in ce - us exam ( white arrows ) .
c. the same patient during vcug examination ( black arrows ) in some cases , we noticed a quick destruction of uca due to increased intravesical pressure in children who did not cooperate and were crying .
some children had problems with postponed voiding phase , which excluded the possibility of ce - vus use in these cases , while vcug could still be performed .
these specific uca characteristics minimize the usefulness of this method for evaluation of the urethra during voiding , predominantly in children who are unable to cooperate .
vcug and ce - vus are comparable methods in diagnosis of vur , and can be performed alternatively in selected groups of patients .
however , some limitations of ce - vus must be remembered , especially technical problems .
the lack of the comparison of both methods including x - ray and ce - vus in urethra evaluation could be viewed as a limitation of our study .
we decided not to repeat the catheterization in our study to evaluate the urethra for each of the studied methods separately .
the study was financed from the means of the national science centre , granted on the basis of decision no .
authors do not report any financial or personal connections with other persons or organizations , which might negatively affect the contents of this publication and/or claim authorship rights to this publication . | backgroundthe invasiveness and exposure to radiation in voiding cystourethrography led to the introduction of alternative methods of diagnosis of vesicoureteral reflux , including contrast enhanced voiding urosonography . while there is a limited number of studies comparing these methods using new generation ultrasound contrast agents , none of them compared both methods simultaneously .
this study is aimed at assessing agreement between contrast enhanced voiding urosonography with second - generation ultrasound contrast agents and voiding cystourethrography.methodsfrom april 2013 to may 2014 , 83 children ( 37 female and 46 male ) , mean age 3.5 years , age range from 1 month to 17.5 years , underwent prospective simultaneous assessment by contrast enhanced voiding urosonography and voiding cystourethrography , with a total of 166 uretero - renal units evaluated.resultsthe sensitivity of voiding cystourethrography and contrast enhanced voiding urosonography were comparable , amounting to 88% , however , neither reached 100% for the entire studied population .
the negative predictive value of voiding urosonography and voiding cystourethrography was 97% , and there was no difference between both methods.conclusionvoiding cystourethrography and contrast enhanced voiding urosonography are comparable methods in diagnosis of vesicoureteral reflux , and can be performed alternatively . however , some limitations of contrast enhanced voiding urosonography must be remembered . | Wprowadzenie
Materia i metody
Wyniki
Wniosek
Background
The aim of the study
Methods
Statistics
Results
Discussion
Conclusions
Limitations
Conflict of interest |
diffuse axonal injury ( dai ) is a brain injury characterized mainly as axonal injury of the white matter .
it often follows brain trauma , which causes wide - ranging denaturation of white matter , focal hemorrhage , emergence of axonal retraction balls , and microglia clusters .
dai is often accompanied by other brain injuries , and this has caused patients severe brain damage or even placed them in a persistent vegetative state . according to reports made in recent years , the mortality rate of dai is 42%62% [ 1 , 2 ] .
dai has been as an independent category of disease accepted by neurosurgery academic . however , there are currently no standard diagnostic criteria , and the relationship to other brain injuries needs to be investigated further in order to develop better clinical treatments for dai .
below , the authors review the concept , pathological mechanism , and methods of clinical diagnosis of dai .
it has gone through three conceptual stages in its history . the first period began in 1956 , when strich studied autopsies from 5 patients with severe closed brain trauma and proposed that degeneration of the diffuse white matter might be attributed to the physical damage to nerve fibers .
the second period began in 1961 , when this strich studied 20 patients who had died of brain trauma .
he found that the shearing force of the rotational acceleration of head movement ( one of the main causes of brain injury ) caused the nerve fibers to break and evoked diffuse degeneration of hemisphere and brainstem .
the third period began in the 1980s , when adams and gennerelli studied the mechanism of development and clinical pathology of dai thoroughly and made prominent achievements , which were given great consideration when the international academic community selected a final name for this condition .
it takes place after external injury involving shearing force , and it mainly manifests in the form of focal axonal changes and axonal breakage . and it can be divided into primary and secondary axonal injury .
the pathological mechanism of dai is very complicated , but a clear understanding of the pathological mechanism is very important to diagnosis , clinical treatment , and prognosis ; pathological characterization has become a hot topic in neurosurgical research .
the main cause of primary axonal injury was axonal breakage , retraction , and the formation of what is called axon retraction balls because of the shape of the swelling at the end of the axonal axis , which was caused by the external shear force and tension .
the formation of these axon retraction balls was believed to lead to the final breakage of the axon .
currently , it is thought that the axon retraction balls cause axon breakage , so interrupting protein transport , and the individual axon retraction ball has been observed under microscopy at the end of broken axons . however , multiple recent studies have shown that the site of instant , strong shearing force or tension within the brain does not always match the site of actual injury .
animal studies have shown there to be no axon breakage immediately after brain trauma , and pathological examination suggested that the myelin of the axons had remained intact [ 36 ] .
this has sparked debate over whether it is suitable to assess the number of injured axons by determining the total number of axon retraction balls after onset of dai .
after external instant shear force and tension act on the brain , the permeability of the axon membrane changes , and large amounts of ca enter the cells . the anterograde transport of axon plasma is gradually converted to retrograde transport , so activating the cysteine protein signal pathway and caspase-3 .
the inherent cellular calpain inhibitor calpastatin is hydrolyzed . a relatively high level of activated calpain accumulates within the cell , and this degrades the axonal cytoskeleton network .
recent studies have shown that influx of ca and degradation of the axonal cytoskeleton network are progressive events , during which axons usually maintain their morphology several hours after injury [ 710 ] .
spectrin , also called cell ghost , is a structural protein found on the inner side of the membrane .
it not only supports the lipid bilayer but also maintains the shape of red blood cells .
it forms a transformable network beneath the plasma side of the membrane and so maintains the biconcave disk shape of red blood cells . during the early stage of injury , calpain - mediated hydrolysis of spectrin in focal axon
was observed , as indicated by single and double markers ' under immunohistological examination via light microscopy and electromicroscopy .
most axons show signs of calpain - mediated hydrolysis of spectrin 1 - 2 h after the injury .
related pathological changes include loss of microtubules , swelling of the mitochondria , and neurofilamentous knots , which indicate that calpain - mediated hydrolysis of structural protein and degradation of the cytoskeleton play important roles in the development and progression of dai pathology [ 1113 ] .
mitochondrial damage after onset of dai mainly includes swelling and breakage of the mitochondrial crest and membrane .
ca influx leads to changes in the permeability of the mitochondrial membrane and affects the opening of the switching pore in said membrane .
the intake of small molecules causes the mitochondria to swell and break , which further not only disrupts the energy metabolism and ion homeostasis but also releases caspases and the activators of apoptosis , so triggering caspase - mediated progressive cell death .
impairment of the mitochondria , imbalance in ion homeostasis , the release of proapoptotic factors , and activation of caspases are key contributors to the high mortality and poor prognosis of dai .
it has drawn a great deal of attention because it can be converted to toxic -amyloid ( a ) after protease hydrolysis .
the use of immunohistology to assess changes in app in axons is the gold standard of neuropathology and trauma model diagnosis of dai [ 18 , 19 ] .
once pathological changes take place , the anterograde transport of app becomes disrupted , which causes focal aggregation of app .
increasing amounts of evidence show that changes in glia cells play very important roles in the development and progression of dai .
the morphological and functional changes in astrocytes , microglia , and oligodendrocytes that take place after onset of dai and are called glial reaction .
glial cells become activated and involved in eliminating and engulfing particles expelled from the site of injury , extend projections to fill in cavities , form glial scars , and produce matrix metal proteins ( mmps ) to reconstruct damaged extracellular matrices after the progression of dai .
glia cells also express insulin - like growth factor-1 , epithelial growth factor , and other neurotrophic growth factors in order to decrease the rate of neuronal death and neural injury after the progression of dai [ 20 , 21 ] .
astroglia ( as ) is a major type of glial cells in the central nervous system ( cns ) originating from neural ectoderm .
the distribution of as in the brain was regular ( gfap positive cells in hippocampus and dentate gyrus in obvious rules ) .
this kind of order contributes to the position of the fixed relationship and the function of stable relationship between as and neuron . and as may also be involved in the complex functions of the brain activity , including learning and memory .
recently , it showed that as clears hemorrhage in the early damage and degeneration necrosis tissue with macrophages and thereby promotes wound repair [ 22 , 23 ] .
corresponding to different neurotransmitters and neuropeptide , there are many receptors in as , such as 5-ht and -gaba . in recent years
we thought that it ( at least under the condition of in vitro ) has almost all possible neurotransmitters functional receptors .
after being damaged , neurons produce more neurotransmitters than normal , so the receptors on the as can upregulate and produce more growth factors to promote repairing of injury .
oligodendrocyte ( olg ) is myelin glial cells in the central nervous system and rich in grey and white matter of brain and spinal cord .
mechanical damage , ischemia , or axonal degeneration can cause the damage and apoptosis of olg ; otherwise , there is great relevance between axonal degeneration after brain injury and the apoptosis of olg . and
the fas and p75 receptor activation may be involved in apoptosis . however , glial cells become activated further , to the point of overactivation , as dai progresses . overactivated glial cells continuously release inflammatory factors , such as il-1 and tnf- , and they release oxygen free radicals and cytotoxic substances , which elicits inflammatory responses , causes oxidative stress in brain tissue , and directly or indirectly induces neuronal death .
overactivation of glia cells causes the release of chondroitin sulfate proteoglycan , prevents the glia cells from reconstructing the extracellular matrix , inhibits axon growth , and weakens the ability of glial cells to eliminate products expelled from the site or injury . in this way , overactivated glial cells promote neuronal injury .
activation of glia cells can also promote neuron - glia and glia - glia interactions .
previous studies have demonstrated that the chemokine cxcl-12 , which is released from astrocytes , promotes the release of glutamate , which further promotes the release of large amounts of tnf- from microglia .
high concentrations of tnf- impair the ability of microglia to eliminate glutamate , and this causes excitatory toxicity and injures neurons .
astrocytes also release the anti - inflammatory factor il-10 , which inhibits the release of tgf- from microglia and promotes the maturation of oligodendrocytes [ 2730 ] .
however , it remains unclear whether the activation of glial cells promotes injury or repair .
ct allows rapid and reliable location of focal hemorrhages related to axonal injury , but it is difficult to find injuries other than hemorrhages , especially if they are small in size or involve needle - like bleeding .
traditional mri examination not only allows rapid location of hemorrhages , but it is also a sensitive and reliable way of locating nonhemorrhages .
it has better resolution than ct scans and it is especially suitable for injuries to the posterior cranial fossa and deep white matter .
however , it still has a high rate of false negative results for small lesions and mild dai .
moreover , patients are often unable to complete the examination due to the long time requirements .
as medical science has progressed , more accurate methods of diagnosing dai have been developed .
dwi involves using the anisotropy of protein to identify changes in white matter after onset of dai .
studies have shown dwi to be an accurate method of examining nonhemorrhage injuries , especially at the sites within the cranial vault . however , this method is often not sufficiently accurate for the examination and diagnosis of injuries to the corpus callosum and grey matter .
dti , which was developed as an improved form of dwi , can be used to evaluate nerve alignment , injury context , and the microstructure of white matter effectively .
it can also allow direct observation of the nerve alignment and the collection of abnormal morphology information regarding major nerve fibers . in this way
, dti can detect dai in a highly sensitive way and allow estimation of the time elapsed from injury to examination .
gre - swi can detect more minor hemorrhages and so indicate the severity of dai more accurately than other methods can , which makes it especially suitable for early diagnosis of dai .
this new imaging method is the use of magnetic susceptibility which is different between different organizations and imaging technology . and
the key to imaging is magnetic sensitive material ; in some tissues , such as venous blood , bleeding , and calcification , the magnetic susceptibility is different from that of surrounding tissues . on the one hand it can shorten t2 ;
on the other hand , it can lead to blood vessels and surrounding tissues of different phase contrast .
diffuse axonal injury ( dai ) accounts for more than 30% of severe craniocerebral injury and is the main causes leading to a vegetative state or serious nerve dysfunction .
further clinical study found hemorrhage of dai with worse prognosis than less bleeding . however , both ct and routine mri are not sensitive to the smaller hemorrhage stove .
gre - swi is very sensitive to hemoglobin metabolites , such as dna , methemoglobin , hemoglobin , and hemosiderin .
so , gre - swi can detect these metabolites more effectively than conventional mri [ 31 , 32 ] .
so the gre - swi play an important role in the evaluating , treating of traumatic brain injury , and prognosis judging .
although gre - swi is valuable for finding the minor hemorrhage in brain clinically , it still can not make difference between other minor hemorrhages caused by patients related diseases , such as hypertension . and the acquisition and processing technology still needed further improvement , to improve the scanning speed , reduce artifacts , and improve the signal - to - noise ratio .
animal studies have shown that rats with mild dai have abnormal neural electrophysiology regardless of whether they have sustained any axonal injury .
other studies have shown pathological changes and decreases in action potential in the axonal axis of the corpus callosum of mice with brain trauma .
the action potential of both myelinated nerve fibers and unmyelinated nerve fibers in the corpus callosum has been found to decrease . among those nerve fibers ,
myelinated fibers were found to recover their action potential gradually as their axons were repaired , while unmyelinated nerve fibers did not [ 3438 ] .
these findings indicated that the abnormal action potential of unmyelinated nerve fibers may play an important role in the disability associated with dai .
currently , commonly used biochemical markers for acute dai diagnosis and analysis of the conditions and prognosis associated with dai include -app , spectrin , and its decomposition products sbdp145 and sbdp150 .
other markers include neurofilaments and the phosphorylated products of their tau subunits and hydrolyzation of myelin basic protein .
the detection of -app is currently considered the gold standard of dai examination in forensic and laboratory settings . it is often used for early diagnosis of dai . under normal conditions , the -app present in axons can not be detected using immunohistochemistry . however , after onset of dai , the disruption of transportation through the axoplasm causes -app to aggregate in the axons , bringing its concentration up to detectable level .
this makes it suitable for use as a marker for early diagnosis of dai . however , detection of -app by immunohistochemistry after onset of dai can cause underestimation of the scope of axonal injury . through more in - depth studies ,
detection of -app695 , an isoform of -app , could provide more reliable and sensitive diagnosis of dai .
attention must be paid to diseases that can cause clinically abnormal axonal metabolism , in which -app has been shown present via immunohistochemistry . in this way , patients ' disease history must be taken into consideration , which would increase the accuracy of diagnosis via immunohistochemical examination of -app .
the spectrin - ii subunit is present within the neuron body , dendrite , and axons . along with neurofilaments and microtubule - associated proteins
the spectrin - ii subunit of calpain degradation products ( sbdp ) detected in cerebral cortex , cortex medullary junction , corpus callosum , and cerebrospinal fluid following dai mainly include sbdp-150 and sbdp-120 .
the trends in the changes of the concentrations of sbdp-150 and sbdp-120 in the cerebral cortex and corpus callosum have been shown to be similar , which indicate that , after onset of dai , calpain - induced necrosis is an important pathological mechanism of dai
. however , the trends in the concentrations of sbdps in cerebrospinal fluid are not synchronous with those of the brain , and the trends in the concentrations of degradation products from different subunits of spectrin are also different .
one possible reason for this is that the proteins released from the brain parenchyma must be transported into the cerebrospinal fluid via the intercellular fluid , while proteins released from injured neurons in the subarachnoid space can be released directly into the brain . in this way
, the measurement of the expression of different subunits of spectrin expression could be used to assess the severity of dai , show whether it is associated with focal or diffuse functional impairment , and provide some basis for predicting the pathological mechanism of dai .
neurofilaments are composed mainly of light chains ( nf - l ) , medium chains ( nf - m ) , and heavy chains ( nf - h ) .
after onset of dai , the spatial configurations of nf - l , nf - m , and nf - h peptides were different , according to the severity of dai . in mild and moderate dai , three types of nf subunits presented focal disorder .
phosphorylated neurofilament was hydrolyzed and finally resulted in neurofilament collapse . because nf - h can be detected in serum after onset of dai and increased from 6 h , peaked at 12 h and 48 h , and decreased to normal level on day 7 [ 42 , 43 ] .
nf - m must be investigated further if it can be used as a specific marker of dai diagnosis .
each molecule of tau contains 2 - 3 phosphoric acid groups . overphosphorylated tau groups lose their normal transport function in axons and in turn inhibit the assembly and promote dissemble of microtubule , finally causing axonal breakage .
after onset of dai , tau was depolymerized to c - tau by calpain , which can be detected in large amounts in cerebrospinal fluid .
the detection level of c - tau in the cerebrospinal fluid is negatively correlated to the severity of dai of patients in clinical settings [ 44 , 45 ] . in this way
, the detection of c - tau in cerebrospinal fluid was used to quantitatively evaluate the severity of axonal injury .
investigation has shown that once the c - tau level in patients ' cerebrospinal fluid reaches 2.126 mg / ml , the accuracy of prognosis of the mortality rate reaches 100% and specificity rises above 80% .
however , c - tau detected in serum was not found to facilitate effective evaluation of prognosis .
for this reason , the detection of c - tau levels in the cerebrospinal fluid is considered one of the most suitable biochemical markers for clinical diagnosis of dai .
myelin basic protein ( mbp ) is the main protein in myelin in the central nervous system ( cns ) .
it is present on the plasma side of myelin , where it keeps the protein 's structure and function stable .
it is specific to nerve tissue . because of the blood - brain barrier ( bbb )
, mbp is readily released into cerebrospinal fluid , and a very small amount of mbp is released into the blood .
after onset of dai , the cns is damaged and the bbb can be completely destroyed .
the changes in the permeability of bbb result in the increase of mbp levels in serum .
determination of mbp level in serum can indicate its quantity in a timely manner , and the samples for determination are easy to collect .
scholars both within and outside of china have reported that mbp could be a suitable index of the severity of cns injury . in the same way
, the determination of mbp levels in serum and cerebrospinal fluid could facilitate preliminary judgement of the severity of dai and allow objective evaluation of the progression and prognosis of dai .
however , the sensitivity of the detection of serum mbp is not currently ideal and the use of mbp detection in clinical settings is limited .
other biomarkers for diagnosis of dai include cyclooxygenase-2 , aquaporin-4 , inflammatory reaction factors ( such as il-1 , il-6 , and tnf ) , and basic fibroblast growth factor .
these factors can facilitate diagnosis of continued injury , inflammatory responses , and the development and progression of dai .
although neuropsychological assessment as a noninvasive form of diagnosis can not be used to quantify dai , it can be used to indirectly show the efficacy of clinical treatment according to the differences in consciousness and cognitive disorders of patients in acute and subacute states .
studies have shown that cognitive disorder is related to the site of injury , correlated in some extent to the state of the white matter connected to specific functional areas .
increasing numbers of investigators have attempted to discern clinical efficacy directly through digitalized neuronal evaluation .
according to the different standards , a variety of partition can be made to the neuropsychological test .
the most common ones are divided into a single test and battery of tests . and
the test concludes infants , children , and adults , three versions . and the test is divided into part for verbal test and others for nonverbal test
. the revised hrb test battery mainly surveys the following ten aspects : category test , touch operation test , music rhythm test , finger tapping test , halstead - wepman aphasia screening test , voice perception test , on one side of the edge test , grip strength test , the attachment test , and perceptual disorder test .
this set of tests use demarcation points as the norm ( the critical points ) to distinguish pathology .
then according to the abnormal test counting damage index damage index = abnormal test number / total number .
the first version includes 269 projects , a total of 11 subtests . the second version added intermediate memory subtest .
there are 11 subtests that constituted the first edition of lnnb and include sports test , rhythm test , touch test , visual test , feeling type words , expressive words , writing test , reading test , math quiz , memory test , and intellectual processes test .
and lnnb has three additional scales , as the disease symptoms characteristic scale ( qualitative scale ) , the left hemisphere lateralization of scale , and right side of the scale .
each project of lnnb adopted 3-level scoring mode : 0 is normal , 1 represents borderline state , and 2 indicates exception . | the current work reviews the concept , pathological mechanism , and process of diagnosing of dai . the pathological mechanism underlying dai is complicated , including axonal breakage caused by axonal retraction balls , discontinued protein transport along the axonal axis , calcium influx , and calpain - mediated hydrolysis of structural protein , degradation of axonal cytoskeleton network , the changes of transport proteins such as amyloid precursor protein , and changes of glia cells . based on the above pathological mechanism
, the diagnosis of dai is usually made using methods such as ct , traditional and new mri , biochemical markers , and neuropsychological assessment .
this review provides a basis in literature for further investigation and discusses the pathological mechanism .
it may also facilitate improvement of the accuracy of diagnosis for dai , which may come to play a critical role in breaking through the bottleneck of the clinical treatment of dai and improving the survival and quality of life of patients through clear understanding of pathological mechanisms and accurate diagnosis . | 1. Introduction
2. Concept
3. Pathological Mechanism of DAI
4. Diagnosis of DAI |
cutaneous leishmaniasis ( cl ) is an infectious disease caused by the leishmania parasite that is transmitted through the bites of phlebotominae sand flies .
cl is characterized by broad clinical polymorphism varying from localized to diffuse and disseminated lesions .
localized cl ( lcl ) is the most prevalent clinical manifestation worldwide , characterized by the appearance of a skin lesion at the vector sting site .
the lesion occurs after reproduction of the parasites into the dermis , which generates a granuloma .
the granuloma is initially manifested as small papule that progressively increases in size to form a rounded nodule . as a consequence of the parasite virulence and host immune response , the nodules show necrosis in the center and become ulcers characterized by a round form , with high and clear borders , an indurated base and granular background , painless and with a scab firmly attached to the base .
overinfection with bacteria or fungi , often caused by empirical treatments , produces purulent and painful ulcers .
characteristic scars with hyper- or hypochromic edges , commonly called onion bulb scars , appear after treatment .
nodular lesions sometimes become scaly epidermal plaques or warty lesions . in some patients , the parasite may spread via lymph and blood to the skin of different anatomical regions , particularly the face , chest and upper limbs , where the parasite reproduces widely and causes disseminated leishmaniasis ( dl ) or diffuse cutaneous leishmaniasis ( dcl ) . although these two clinical forms can be clearly differentiated ( see table 1 ) , some authors consider them as synonymous , which makes a meta - analysis of the literature review difficult . here , we report a series of dl patients attended at the pecet , university of antioquia ( medelln , colombia ) . a literature review focusing the attention on the available information to differentiate dl and dcl
twenty - two patients ( 85% ) were men ; 20 patients ( 77% ) were of mixed race , 4 patients ( 15% ) were black , and 2 patients were indigenous ; their age ranged from 4 to 61 years ( mean 32 years ) .
twenty - five patients ( 96% ) were from the northwest of colombia ( antioquia , choco and cordoba states ) , but only 2 patients came from the southeast of the country . only 1 patient evidenced hiv coinfection .
parasite cultures were positive in 16 patients , while the remaining 11 cultures were negative .
leishmania ( viannia ) panamensis was identified as the causative agent in 15 isolates ; the last isolate was identified as viannia subgenus , but no species was determined .
this leishmania species distribution is similar to that observed for patients with lcl from the northwestern colombian region , where 70% of the strains circulating are l. ( v. ) panamensis and 30% correspond to l. ( v. ) braziliensis , whereas in the southeastern region , 80% of the circulating species are l. ( v. ) braziliensis as identified by monoclonal antibody techniques and pcr - rflp ( unpublished data ) .
all patients met the diagnostic criteria of having 10 or more polymorphic lesions in at least 2 parts of the body surface .
the number of lesions for each patient varied between 12 and 294 ( 21 patients with 100 lesions or less , 3 patients had more than 100 lesions and less than 200 , and 4 patients had more than 200 lesions ; table 3 ) .
the evolution time since the appearance of the first lesion to the spreading was more than 2 weeks .
in most patients , the primary lesion was plaque , and the secondary lesions ( disseminated ) were nodules , papules and plaques , with different sizes but smaller than 2.0 cm in diameter . only 1 patient had frank ulcers ( fig . 1 , fig . 2 , fig . 3 , fig .
seven patients ( 25% ) had nasal mucosal involvement consisting of ulcers , scabs or septal perforation indicating an important frequency of mucosal involvement .
the montenegro skin test was positive in 18 of 21 patients ( 84% ) with an induration size that varied between 5 and 12 mm ( average 6.8 mm ; table 2 ) , suggesting no complete anergy of cellular immune response .
cell proliferation and t cell subpopulation in peripheral blood samples were evaluated only in 4 patients who had absolute values of t cell and lymphoproliferative response within the reference values .
however , the percentages of t cell cd3 + , cd4 + and cd3+cd4 + subpopulations were below the reference values , whereas the percentage of naturally occurring regulatory t cells ( cd4+cd25+foxp3 + ) were increased .
five of the 27 patients ( 19.3% ) had diabetes mellitus , obesity , vitiligo , hiv / aids and leukemia as baseline comorbidities , which could favor the spread of the parasite . in 92% , their immunosuppressive condition was not identified , which could facilitate the spread of the parasite since most of patients were farmers from rural areas .
only 2 patients had a clinical condition - based immunosuppression ( hiv and leukopenia ) .
twenty - two patients were treated with intramuscular meglumine antimoniate at a dose of 20 mg / kg / day for 20 days ( table 3 ) .
nineteen of these 22 patients ( 86.3% ) were cured with a single treatment cycle of meglumine antimoniate , while 3 patients did fail .
one of these 3 patients was cured with a second cycle with topical amphotericin b ( anfoleish ) applied twice daily for 28 days , and the other 2 patients were cured with a second cycle with oral miltefosine at doses of 22.5 mg / kg / day for 28 days .
one of these 2 patients had been treated before with amphotericin b deoxycholate 1 mg / kg daily only for 9 days because of renal toxicity . among the remaining 7 patients , 2 of them
were cured with 4 applications of intramuscular pentamidine at a dose of 3 mg / kg / day ( table 3 ) ; another patient , who had 103 lesions , was cured after treatment with pentamidine combined with topical amphotericin b applied as before .
another patient was cured with miltefosine alone , and the last patient , who had hiv / aids coinfection , drug abuse , kaposi 's sarcoma , extrapulmonary tuberculosis , cryptococcal meningitis and poor adherence to antiretroviral therapy , was treated with liposomal amphotericin b combined with miltefosine ; this patient showed partial clinical improvement but subsequent appearance of new skin lesions and extensive mucosal involvement .
dl is characterized by an initial injury into the dermis followed by a high number of skin lesions ( > 10 polymorphic lesions ) in at least two parts of the body surface , with or without mucosal involvement [ 2 , 3 ] .
dl has been described in brazil , venezuela , guyana and colombia , with a significant increase in the number of cases in highly endemic places as the brazilian north , colombo - brazilian amazon and colombian northwest .
this clinical manifestation is caused by leishmania species of the subgenus viannia , mainly l. ( v. ) panamensis , l. ( v. ) braziliensis and l. ( v. ) guayanensis .
patients suffering dl describe the initial appearance of a single lesion ( nodule or ulcerative plaque ) , presumably located in the vector bite site .
weeks or months later , as a consequence of parasite dissemination , polymorphic lesions ( isolated or confluent ) , different in size and growth rate , appear in remote anatomic areas from the initial lesion that may cover the entire body surface , except armpits and inguinocrural region ; lesions in the face may become disfiguring .
associated to the skin lesions , mucosal involvement or symptoms such as fever , chills and lymphadenopathy may occur [ 2 , 4 ] . dissemination may occur after therapy with immunosuppressive drugs .
the pathogenesis of dl is not well established . however , partial inhibition of specific cellular immunity against the parasite has been demonstrated . a decrease in cd4 + t cells in peripheral blood with partial absence of t cell response to leishmania antigen , evidenced by a mildly reactive ( 3 or 4 mm induration ) or positive ( > 5 mm ) montenegro skin test , is observed .
a low production of the type th1 cytokines ifn- , tnf- , il-10 and il-5 , which favor the spread of the parasite , is also registered .
histological examination of the lesions can reveal the presence of a granuloma composed of lymphocytic infiltrates with very few or no parasites [ 4 , 7 , 8 ] .
a decrease in the percentage of cd3+cd4 + t cells and an increase in the percentage of regulatory t cells could affect the immune response mediated by t cells because it has been shown that the regulatory t cells cd4+cd25+foxp3 + ( known as natural regulatory t cells ) are potent suppressors of acquired immune response , as is the immune response mediated by t cells [ 9 , 10 ] .
a decrease in the percentage of activated cd4 + t cells in the blood of patients may affect the cellular immune response associated with a decrease of the specific local cellular response against some leishmania species .
the diagnosis of dl as well as other clinical forms of cl is based on the observation of the parasite in smears or aspirates from the lesion . in most cases ,
the treatment of dl is based on systemic administration of pentavalent antimonials ( 20 mg / kg / day for 20 days ) , miltefosine ( 22.5 mg / kg / day for 28 days ) and amphotericin b both deoxycholate ( 0.71 mg / kg / day for 30 days ) or liposomal ( 3 mg / kg / day for 1014 days ) , although the liposomal form is preferred for the lower toxicity .
therapeutic response may also vary from poor to good , depending on the leishmania species .
thus , for example , the percentage of cured patients with dl by l. ( v. ) braziliensis treated with 1 course of antimony therapy for 30 days in its highest dosage ( 20 mg / kg / day ) is 24% , while in patients with dl by l. ( v. ) panamensis , the cure rate is 86.3% , as shown here . with liposomal amphotericin use ( dose ranging from 17 to 37 mg / kg ,
as shown in this work , pentamidine at a dose of 3 mg / kg / day ( 4 applications ) is also a good option to treat dl even in cases having a high number of lesions . in endemic areas for leishmaniasis
, dl is considered as an opportunistic infection mainly in hiv positive patients in whom therapeutic failures and relapses are frequent .
differential diagnosis of dl include diseases such as psoriasis , histoplasmosis ( and other relevant deep mycoses in immunosuppressed patients ) , pemphigus , pityriasis rosea and lupus but also other cutaneous forms of leishmaniasis such as dcl and post - kala - azar dermal leishmaniasis ( pkdl ) .
dcl was described for the first time in venezuela by convit and lapenta in 1948 .
this clinical manifestation of dcl is associated with leishmania species of the leishmania subgenus , mainly l. ( l. ) amazonensis ( in the new world ) and l. ( l. ) aethiopica ( in the old world ) [ 17 , 18 ] .
dcl appears during the first decades of age , with periods of remission and frequent relapses .
the montenegro skin test is predominantly negative , and histologically , granulomas with few lymphocytes and abundant parasites are observed .
dcl is more severe because a complete inhibition of specific cellular immunity occurs and the therapeutic response is poor and therefore , relapses occur more frequently [ 19 , 20 ] . in dcl ,
temporary improvement has been observed in venezuela using immunotherapy with bcg and heat - dead l. ( l. ) amazonensis promastigotes , combined with other drugs such as pentavalent antimonial , amphotericin b and miltefosine .
however , relapses of lesions make it necessary to use multiple schemes of treatment [ 22 , 23 , 24 ] . in turn
, pkdl is caused by l. ( l. ) donovani in east africa and india .
this disease is characterized by the appearance of rash during weeks or months , followed by macules and plaques especially in the face , upper chest and upper limbs .
, pkdl requires specific treatment , while in african countries , the disease usually heals spontaneously .
although dl has been showing an increase in the number of cases in recent years in countries such as brazil and colombia , this is a rare entity and poorly described in the literature . in this clinical manifestation , anergy is not absolute , lesions heal easily and patients show good response to drugs recommended by the who to treat lcl such as pentavalent antimonials and miltefosine , and therefore , patients have good prognosis .
it is very important to distinguish it from other cutaneous manifestations , mainly from dcl and pkdl , because there are significant differences in etiology , treatment response and prognosis .
the authors state that the patients gave their informed consent complying with all ethical guidelines for human studies . | disseminated leishmaniasis ( dl ) is a poorly described disease that is frequently misdiagnosed as other clinical manifestations of cutaneous leishmaniasis ( cl ) such as diffuse cl or post - kala - azar dermal leishmaniasis .
twenty - seven cases of dl diagnosed between 1997 and 2015 are described .
a higher prevalence was observed in men ( mean age 32 years ) .
the number of lesions per patient ranged from 12 to 294 , distributed mainly in the upper extremities , face and trunk .
the lesions were mostly plaques or nodules .
seven patients had nasal mucous damage , 74% of the patients were of mixed race , 92% lived in northwestern colombia , and leishmania ( viannia ) panamensis was identified as the causative agent in 58% of cases .
eighteen patients recovered with pentavalent antimonial .
the importance of distinguishing dl from those other clinical presentations is based on the fact that disseminated , diffuse and post - kala - azar cl are very different in etiology , clinical manifestations and response to treatment and prognosis . | Introduction
Case Presentation
Discussion
Statement of Ethics
Disclosure Statement |
the prevalence of edentulism has decreased during the last decades , especially in developed countries . however , the level of edentulism is still high in developing countries [ 13 ] .
in addition , more people worldwide are advancing into old age and a growing number of edentulous people are expected .
edentulism has a deep impact on the quality of life , affecting individuals ' physiological , biological , social , and psychological state .
it can also cause a state of depression due to disturbances in speech , esthetics , mastication , and a feeling of inferiority because an important part of the person has been lost .
conventional complete dentures are still the treatment of choice in many cases for both economic and biological reasons . however , a considerable proportion of denture wearers are dissatisfied with their complete dentures . several studies investigated factors that may affect patients ' satisfaction with their complete dentures , such as denture technical quality , condition of the residual ridges , and patient 's gender , age , previous denture experience , and personality [ 5 , 6 , 8 ] .
conflicting results have been reported regarding associations with denture acceptance ; yet emotional and psychological factors seem to play an important role in acceptance of complete dentures [ 4 , 5 ] .
the use of a removable denture depends on the patient 's ability to adapt to the function of the dentures as well as adaptation at the emotional level [ 5 , 6 ] .
the relationship between patient 's personality and denture satisfaction has been investigated and inconsistent findings were reported , regarding the relationship between personality and denture satisfaction [ 46 , 9 ] .
several questionnaires have been used to assess patients ' personality , for example , the shortened version of the minnesota multiphasic personality inventory ( mmpi ) , the cornell medical index ( cmi ) , cattell 's 16pfq form c questionnaire , the revised personality inventory ( neo pi - r ) , the eysenck short scale personality questionnaire ( epq - r ) [ 1215 ] , and the eysenck personality inventory ( epi ) .
it has been noted that some personality traits like neuroticism influence patient satisfaction with a removable denture [ 5 , 1012 , 16 , 17 ] .
long - time complete denture wear often results in reduced occlusal vertical dimension due to residual ridge resorption and acrylic tooth wear .
this is especially true for the mandible . restoring the ovd is an important treatment procedure in prosthetic treatment , especially in edentulous patients .
the aim of our study was to investigate the effect of the patients ' personality on satisfaction with their present complete dentures and after an increase in the ovd by using the arabic version of the epq for personality assessment .
the hypothesis of the study was that personality traits were expected to have an effect on the patients ' satisfaction with the present dentures and after an increase in the ovd .
sixty completely edentulous patients with maxillary and mandibular complete dentures in use ( 22 men and 38 women , mean age 66 years , and range 5075 years ) who were seeking prosthetic treatment for relining of their old dentures or fabrication of new ones were selected from the department of prosthodontics , faculty of dentistry , alexandria university , egypt , in 20092011 .
all patients who had complete dentures with a reduced ovd and an interocclusal rest space of no more than 10 mm participated in the study after giving their informed consent .
the age of their complete dentures ranged from 5 to 16 years ( mean 9 years ) .
the patients included had one or more mild signs of temporomandibular disorders ( tmd ) , that is , masticatory muscle pain during palpation or headache .
patients with temporomandibular joint ( tmj ) clicking and patients with a significant restriction in opening movement of the mandible were excluded .
patients with a systemic disease that possibly affects the masticatory system , for example , rheumatoid arthritis or epilepsy , were also excluded from the study .
the study was approved by the research ethical committee , faculty of dentistry , alexandria university .
the patients were recalled for three visits after the first visit at two - week intervals ( see figure 1 ) .
a clinical stomatognathic examination was performed , including measurement of the opening movement of the mandible and recording of tmj sounds , tmj pain , and/or pain in the masticatory muscles during palpation .
the interocclusal rest space was determined by calculating the difference between rest vertical dimension determined phonetically and ovd with the two - dot technique using a ruler .
the patients ' personality was assessed by using the arabic version of the eysenck scale personality questionnaire .
all the patients were interviewed by the same psychologist , who presented the questionnaire to the patients and recorded their answers .
the questionnaire consisted of 90 questions with yes / no answers , and it yielded scores for each of the major personality traits : psychoticism , extrovertism , neuroticism , criminality , and lie scale .
the patient 's attitude toward his / her present dentures before relining and restoration of the ovd was determined by asking questions related to chewing efficiency , speech , and overall satisfaction ( questionnaire i ) .
chair - side relining of poorly fitting mandibular denture was done using self - curing acrylic resin ( hardliner , promedica , neumnster , germany ) [ 22 , 25 ] .
the ovd was restored gradually , 2 mm during the second visit and up to 5 mm during the third visit , according to the interocclusal rest space of each patient , by applying autopolymer acrylic resin to the occlusal surfaces of the posterior teeth of the mandibular denture ( snap parkell , ny , usa ) .
evaluation of the patients ' denture satisfaction after restoration of the ovd was assessed using a second comparative questionnaire ( questionnaire ii ) .
an independent interviewer , who did not participate in the clinical examination or the treatment procedures , presented questionnaires i and ii to the patients .
the interviewer read each question to the patient and recorded the patient 's answers . all the clinical examinations and treatment procedures
were performed by the same dentist specialized in prosthetic dentistry ( smf ) . the statistical package for social sciences ( spss / version 17 ) software was used for data analysis .
the chi - square test served for analysis of categorical data and comparison of the patients ' satisfaction and different personality traits .
table 1 shows the patients ' overall satisfaction with their complete dentures at the first appointment .
two - thirds ( 73% ) of the patients showed slight to complete dissatisfaction with their dentures .
most of the patients ( 83% ) used their dentures always / almost always for eating , although 70% of them mostly / frequently experienced chewing discomfort and 67% rarely felt it easy to chew hard food .
over half ( 53% ) of the patients experienced pain in their jaws and 58% reported jaw aching or stiffness in the morning .
after restoration of the ovd and denture relining , the patients ' perception of their dentures showed improvement in chewing ability ( 67% ) and chewing comfort ( 53% ) , and they perceived also improvement in chewing hard food ( 52% ) ( table 2 ) .
the patients also reported improvement in jaw aching or stiffness in the morning ( 27 patients ) as well as in jaw pain ( 19 patients ) .
when the levels of satisfaction with the original dentures before and after dentures relining and restoration of the ovd were compared , a significant increase in the patients ' satisfaction was observed ( p < 0.05 ) ( table 3 ) .
neuroticism correlated with the patients ' satisfaction with their original dentures before and after restoration of the ovd and relining ( p < 0.05 ) .
two - thirds ( 29/44 , 66% ) of the patients who were unsatisfied with their original denture had a high score on neuroticism , while all the satisfied patients had an average neuroticism score ( table 4 ) .
no correlation between personality traits of psychoticism and extrovertism and the patients ' satisfaction with their original denture was seen ( table 4 ) .
after an increase in the ovd and relining , a significant association between the level of the patients ' satisfaction and psychoticism was observed ( p < 0.05 ) . of the unsatisfied patients ( n = 12 ) , 10 had a high score on psychoticism ( table 5 ) .
after denture relining and restoration of the ovd , 12 patients were unsatisfied with their dentures and nine of them had a high score on neuroticism ( table 5 ) .
in the present study a significant increase in the patients ' satisfaction after chair - side relining of poorly fitting mandibular dentures and restoration of the ovd was observed .
our results confirm the findings of previous studies showing that dissatisfaction with dentures in addition to the retention and stability of the dentures is maybe associated with emotional instability or neuroticism [ 1012 , 16 , 17 ] .
psychological factors can affect patients ' acceptance of a denture , and therefore a personality assessment could be beneficial in predicting satisfaction with a complete denture .
this result agrees with the finding of the previous studies , which found that most patients with a modified denture perceived improvement or no change [ 24 , 26 ] .
most patients with old dentures accepted a gradual increase in the ovd , even if they were used to their old dentures with a reduced ovd .
this could also be explained by the improvement in chewing functions and the gradual increase in the ovd performed in this study , which might be tolerated better by the patients than an increase in one step .
the personality trait of psychoticism was not significantly related to patients ' satisfaction with their original dentures .
, a high psychoticism score was related to patients ' dissatisfaction after relining and restoration of the ovd of their old dentures .
a person with a high psychoticism score tends to behave impulsively , being insensitive , aggressive , and finding it difficult to adapt [ 28 , 29 ] .
therefore , psychoticism had no effect on patients ' satisfaction with their old dentures because they were used to them , while it affected their acceptance of a change in their dentures , that is , an increase in the ovd .
another explanation might be the evaluation of the patients ' satisfaction with the increased ovd after only two weeks , which is a short period for patients with a high psychoticism score to adapt to a change in their dentures .
this finding is in line with a study that found a presence of a difference in the relationship between personality profiles and satisfaction before and after treatment .
a person with a high neuroticism score has been described as being a worrying individual , frequently depressed , and overtly emotional and having a greater tendency to complain about his / her denture [ 27 , 28 ] .
some studies have shown a significant negative association between neuroticism and patient satisfaction with a denture [ 5 , 10 , 12 , 16 ] .
in addition , vague denture complaints and esthetic complaints about a bulbous face have been found to be related to neuroticism .
it has been noted that neuroticism remained the only trait that maintained a relationship with patients ' satisfaction before and after treatment , while other personality profiles were found to be significantly related to satisfaction ratings after treatment .
other studies found that dissatisfied patients may possess particular personality traits that influence their satisfaction with dentures .
although in these studies the personality trait of neuroticism was not measured , the findings are still in line with our results [ 4 , 11 ] .
an extravert is characterized by being sociable , talkative , outgoing , cheerful , and optimistic ; in contrast an introvert is overly careful , shy , pessimistic , and calm and dislikes company .
this result may be related to the relatively small number of patients with a low extroversion score . however
, this finding agrees with the results of previous studies which suggested that extrovertism was not related to patient satisfaction with dentures [ 12 , 27 ] .
this finding disagrees with a study that found a relationship between the personality trait of extrovertism and functional complaints about the mandibular denture and complaints about a hollow face .
the arabic version of the epq for assessment of patients ' personality was utilized because of its validity and reliability in egypt .
the epq is an effective personality measurement tool which analyzes the characteristics of personality structure .
the strengths of our study were that the personality assessments were done by the same psychologist , the questionnaires were presented to all the patients by the same interviewer , all the clinical procedures were performed by the same dentist , and all the patients completed the study .
the limitations include a relatively small sample size and a lack of patients with a high extrovertism score , since the patients here do not represent the whole population .
patients with a high score on neuroticism were less satisfied with their original dentures and after relining and an increase in the ovd compared with patients with an average score on that trait .
a high psychoticism score was found to be related to patients ' dissatisfaction after restoration of the ovd . | complete denture wearers often find it difficult to accept a new denture .
personality traits are among the factors that possibly affect patient satisfaction with a complete denture .
our aim was to investigate the influence of patients ' personality on satisfaction with their present denture and after an increase in the occlusal vertical dimension ( ovd ) .
sixty edentulous patients with complete dentures ( 22 men and 38 women , mean age 66 years , and range 5075 years ) participated in the study .
the age of their complete dentures ranged from 5 to 16 years .
patients ' personalities were evaluated using the arabic version of the eysenck personality questionnaire .
their satisfaction with their dentures before and after restoration of the ovd and relining of the mandibular denture was evaluated using two questionnaires ( i and ii ) , patients with a high score of neuroticism were less satisfied with their original dentures and after relining and an increase of ovd compared with patients with an average score in that trait .
the personality trait of psychoticism was significant to patients ' acceptance of an increase in ovd ; that is , patients with a high score were less satisfied with their dentures after increase of ovd than patients with an average score .
it is concluded that personality traits affect patients ' acceptance of their complete dentures . | 1. Introduction
2. Materials and Methods
3. Results
4. Discussion
5. Conclusion |
all imaging was performed with a verasonics vantage 128 ultrasound engine ( verasonics , inc . , kirkland , wa , usa ) .
the vantage 128 is a research platform that allows the user to program and control transmit and receive on each element of a linear array with user - developed matlab programs ( the mathworks , inc . , natick , ma , usa ) .
phase - resolved echo data received by each transducer element are digitized at up to 62.5 mhz at 14 bits per sample .
the probe had an elevation aperture of 1.5 mm and was customized to provide an 18-mm focal depth in the elevation axis .
elements were spaced at 80-m intervals along the azimuthal axis to provide an overall lateral dimension of approximately 1 cm . all images and acoustic intensity measurements
we used a calibrated needle hydrophone ( precision acoustics , inc . , dorset , uk ) with 40-m - diameter sensor to measure the acoustic pressure at and around the probe 's elevation focus in plane - wave and conventionally focused modes , where a relatively weak focal ratio of f4 was used .
( typically , f - ratios between 1.5 and 4 are used for b - mode imaging with linear arrays . )
we used a two - cycle excitation to simulate b - mode and a four - cycle excitation to simulate color - flow doppler mode .
we acquired compound coherent plane - wave images of a 0.02-mm - diameter polypropylene surgical thread ( model no .
8065 - 307601 ; alcon laboratories , inc . , fort worth , tx , usa ) coherently compounding 1 , 3 , 5 , 10 , or 50 transmissions acquired at equally spaced angular intervals over 10. an 18-mhz , two - cycle waveform was used for excitation .
we acquired 14 images per imaging condition , from which we determined the snr ( from signal maximum divided by root mean squared background noise ) and the 12-db lateral beamwidth .
images of the posterior pole were acquired from 1 , 3 , 5 , 10 , and 50 successive angles over a 10 range at pulse repetition frequency ( prf ) of 10 khz , so that coherent compound images were formed at 10/n khz , where n is the number of angles .
coherent compound images of the eye were acquired for each value of n and were evaluated qualitatively .
images of the whole eye were acquired by compounding 20 successive angles and compared with images of the same eye acquired with a 10-mhz single - element , mechanically scanned ophthalmic ultrasound system ( aviso ; quantel medical , bozeman , mt , usa ) .
we implemented flash doppler for real - time depiction of blood flow in the context of b - mode images in this mode , two - cycle plane waves were emitted at equally spaced angles over 10 to form b - mode images in real time . at 8.2-ms intervals ,
b - mode acquisition was interrupted and a series of 28 four - cycle plane waves were emitted at a single 12 angle at a 4-khz prf .
doppler analysis was then performed at each pixel position , and color - flow data depicting velocity or power were superimposed upon the grayscale b - mode image in real time .
we developed software to allow high - speed data acquisition followed by postprocessing for high - resolution depiction of slow flow .
we acquired three coherent plane - wave images over an angle of 10 at a 20-khz prf ( 6666 coherently compounded images per second ) for 1.6 seconds .
we postprocessed data with custom software developed in matlab , using techniques similar to those described in reports by mace et al . and demene et al .
in brief , we used a singular value decomposition ( svd ) spatiotemporal filter to suppress clutter signals originating from stationary and slowly moving tissue while retaining signals from moving blood cells .
we then summed the intensities from the blood signal to produce a high - quality power doppler image . by using a sliding analysis window of 76.8-ms duration and a step size of 4.8 ms ( 72-ms overlap between successive analyses )
, we produced a temporal series of images demonstrating flow variation over the 1.6-second period of data acquisition , which was sufficiently long to capture two cardiac cycles .
we used the frequency information of this temporal series to plot spectrograms representing the simultaneous flow speed at various locations as a function of time .
our software allowed b - mode imaging with or without real - time , flash color - flow doppler , allowing identification of anatomy and regions where flow was present .
the user could at any time interrupt real - time imaging to acquire a block of up to 1.6 seconds of plane - wave data for postprocessing to produce high - resolution color - flow power doppler image sequences .
the study followed the principles of the declaration of helsinki , and the research procedure was approved by the institutional review board ( irb)/ethics committee . after
obtaining informed consent , imaging was performed by placing the horizontally oriented probe in contact with the lower eyelid after application of coupling gel ( genteal ; alcon laboratories , inc . ) on the probe surface .
the subject was scanned in a seated position with the eye in a forward or slightly upward direction of gaze , with both eyes open .
data were acquired in a plane encompassing and extending temporal to the optic disc , capturing the optic nerve head ( onh ) and macula region .
plane - wave b - mode , flash doppler , and 1.6-second blocks of plane - wave data for depiction of vascular flow were acquired . in order to perform repeatability measurements , four sets of data from the same location
were acquired and processed and , from the spectrograms , the peak systolic velocity ( psv ) and the end diastolic velocity ( edv ) were measured in the short posterior ciliary artery ( spca ) at a position prior to the branching into distal spcas .
we used a calibrated needle hydrophone ( precision acoustics , inc . , dorset , uk ) with 40-m - diameter sensor to measure the acoustic pressure at and around the probe 's elevation focus in plane - wave and conventionally focused modes , where a relatively weak focal ratio of f4 was used .
( typically , f - ratios between 1.5 and 4 are used for b - mode imaging with linear arrays . )
we used a two - cycle excitation to simulate b - mode and a four - cycle excitation to simulate color - flow doppler mode .
we acquired compound coherent plane - wave images of a 0.02-mm - diameter polypropylene surgical thread ( model no .
8065 - 307601 ; alcon laboratories , inc . , fort worth , tx , usa ) coherently compounding 1 , 3 , 5 , 10 , or 50 transmissions acquired at equally spaced angular intervals over 10. an 18-mhz , two - cycle waveform was used for excitation .
we acquired 14 images per imaging condition , from which we determined the snr ( from signal maximum divided by root mean squared background noise ) and the 12-db lateral beamwidth .
images of the posterior pole were acquired from 1 , 3 , 5 , 10 , and 50 successive angles over a 10 range at pulse repetition frequency ( prf ) of 10 khz , so that coherent compound images were formed at 10/n khz , where n is the number of angles . coherent compound images of the eye were acquired for each value of n and were evaluated qualitatively .
images of the whole eye were acquired by compounding 20 successive angles and compared with images of the same eye acquired with a 10-mhz single - element , mechanically scanned ophthalmic ultrasound system ( aviso ; quantel medical , bozeman , mt , usa ) .
we implemented flash doppler for real - time depiction of blood flow in the context of b - mode images in this mode , two - cycle plane waves were emitted at equally spaced angles over 10 to form b - mode images in real time . at 8.2-ms intervals , b - mode acquisition was interrupted and a series of 28 four - cycle plane waves were emitted at a single 12 angle at a 4-khz prf .
doppler analysis was then performed at each pixel position , and color - flow data depicting velocity or power were superimposed upon the grayscale b - mode image in real time .
we developed software to allow high - speed data acquisition followed by postprocessing for high - resolution depiction of slow flow .
we acquired three coherent plane - wave images over an angle of 10 at a 20-khz prf ( 6666 coherently compounded images per second ) for 1.6 seconds .
we postprocessed data with custom software developed in matlab , using techniques similar to those described in reports by mace et al . and
, we used a singular value decomposition ( svd ) spatiotemporal filter to suppress clutter signals originating from stationary and slowly moving tissue while retaining signals from moving blood cells .
we then summed the intensities from the blood signal to produce a high - quality power doppler image . by using a sliding analysis window of 76.8-ms duration and a step size of 4.8 ms ( 72-ms overlap between successive analyses )
, we produced a temporal series of images demonstrating flow variation over the 1.6-second period of data acquisition , which was sufficiently long to capture two cardiac cycles .
we used the frequency information of this temporal series to plot spectrograms representing the simultaneous flow speed at various locations as a function of time .
our software allowed b - mode imaging with or without real - time , flash color - flow doppler , allowing identification of anatomy and regions where flow was present .
the user could at any time interrupt real - time imaging to acquire a block of up to 1.6 seconds of plane - wave data for postprocessing to produce high - resolution color - flow power doppler image sequences .
the study followed the principles of the declaration of helsinki , and the research procedure was approved by the institutional review board ( irb)/ethics committee . after obtaining informed consent , imaging was performed by placing the horizontally oriented probe in contact with the lower eyelid after application of coupling gel ( genteal ; alcon laboratories , inc . ) on the probe surface .
the subject was scanned in a seated position with the eye in a forward or slightly upward direction of gaze , with both eyes open .
data were acquired in a plane encompassing and extending temporal to the optic disc , capturing the optic nerve head ( onh ) and macula region .
plane - wave b - mode , flash doppler , and 1.6-second blocks of plane - wave data for depiction of vascular flow were acquired . in order to perform repeatability measurements , four sets of data from the same location
were acquired and processed and , from the spectrograms , the peak systolic velocity ( psv ) and the end diastolic velocity ( edv ) were measured in the short posterior ciliary artery ( spca ) at a position prior to the branching into distal spcas .
table 1 shows measurements of acoustic intensity in conventional and plane - wave modes in relation to fda 510k maximum allowable levels .
results show the plane - wave doppler mode to have significantly lower instantaneous and temporally averaged intensities and mechanical index than the conventionally focused mode .
this is particularly the case with pulsed doppler , where in the conventionally focused mode , instantaneous intensity exceeded fda limits even with weak f4 focusing .
. measurements of acoustic intensity parameters for the conventional and plane - wave imaging techniques compared to fda 510k ophthalmic safety limits table 2 shows the snr and 12-db beam width of the point spread function for coherent compound images formed with 1 , 3 , 5 , 10 , and 50 angled plane - wave images .
lateral resolution was the worst for n = 1 , because no angle compounding takes place under this condition . resolution improved with compounding , but was relatively unchanged as the number of coherent additions was increased .
this is expected because lateral resolution is dependent only on the maximum angle range of 10 , which is held constant for n > 1 .
signal - to - noise ratio ( snr ) and 12-db lateral beamwidth , mean standard deviation , of point spread function calculated from coherent compound plane - wave images of a 20-m diameter polypropylene thread produced from n subimages acquired at equal angular increments over 10 range figure 2 shows compound coherent plane - wave images of the onh region obtained using 1 , 3 , 5 , 10 , and 50 plane - wave transmissions acquired over a 10 angle at a prf of 10 khz .
an improvement in snr was evident as the number of plane - wave images per compound image was increased .
compound plane - wave images of the optic nerve head region of a 66-year - old male subject obtained with ( a ) 1 , ( b ) 3 , ( c ) 5 , ( d ) 10 , and ( e ) 50 plane - wave images coherently added to form the final image .
figure 3 shows b - mode images of a human eye obtained with a conventional 10-mhz , single - element , mechanically scanned transducer and with the 18-mhz linear array .
the linear - array image was generated by coherent compounding of 20 angled plane waves over a 10 range .
plane - wave images provided superior sensitivity , demonstrating vitreous inhomogeneities and improved anatomic depiction of the anterior segment , including the anterior chamber and cornea .
the detached posterior vitreous face appeared brighter using the single - element probe , possibly due to its scan geometry and axially symmetric focus .
comparative b - mode images of a 66-year - old male subject obtained with an ophthalmic b - scanner using a 10-mhz single - element probe ( a , b ) versus the 18-mhz linear array by coherent compounding of 20 angled plane - wave images over a 10 range ( c , d ) .
figure 4 shows real - time power and velocity doppler images of the onh region obtained with a 4-khz doppler prf .
we found detection of blood flow in the region of the onh ( central retinal artery and short posterior ciliary arteries ) and choroid to be easily accomplished . at a prf of 4 khz
real - time ( a ) power doppler and ( b ) velocity doppler images of the posterior pole region of a 66-year - old male subject obtained with a 4-khz doppler prf using the flash doppler technique .
b - mode grayscale images were generated by coherent compounding of seven angled plane - wave images over a 10 range .
figure 5 shows compound plane - wave and power doppler images of the onh region obtained from two sets of data .
the figures clearly depict choroidal perfusion over the entire region being imaged and also flow in the central retinal artery and short posterior ciliary arteries . at a 6.66-khz prf
choroidal flow velocities , however , are slower than this , and power doppler is in any case unaffected by aliasing .
a temporal series of images obtained from the sliding window analysis demonstrates flow variation over the cardiac cycle ( movie clip s1 ) .
figure 6 shows flow - speed variation as a function of time in the choroid , central retinal vein ( crv ) , spca , and distal spca .
results show aliasing in the distal spca where the speed is greater than 14 cm / s .
table 3 summarizes repeatability of flow measurements of the spca over four scan sets of one subject .
average compound plane - wave images ( a , b ) , and power doppler images ( c , d ) of the onh region obtained from two sets of data from a healthy 46-year - old female subject .
each set was acquired for 1.6 seconds at 6.66-khz compound imaging frame rate ( three angles over 10 per image ) .
after postprocessing with the plane - wave doppler technique , choroidal perfusion and flow in the short posterior ciliary artery and central retinal vein are visualized .
spectrograms of ( 1 ) choroid , ( 2 ) central retinal vein ( 3 ) , short posterior ciliary artery , and ( 4 ) distal short posterior ciliary artery depict flow velocity variation as a function of time .
aliasing is evident in the distal short posterior ciliary artery where the flow speed is higher than 14 cm / s .
mean , standard deviation , and coefficient of variation of the peak systolic velocity , end diastolic velocity , and resistive index of the short posterior ciliary artery calculated from four scans of one eye
table 1 shows measurements of acoustic intensity in conventional and plane - wave modes in relation to fda 510k maximum allowable levels .
results show the plane - wave doppler mode to have significantly lower instantaneous and temporally averaged intensities and mechanical index than the conventionally focused mode .
this is particularly the case with pulsed doppler , where in the conventionally focused mode , instantaneous intensity exceeded fda limits even with weak f4 focusing .
. measurements of acoustic intensity parameters for the conventional and plane - wave imaging techniques compared to fda 510k ophthalmic safety limits
table 2 shows the snr and 12-db beam width of the point spread function for coherent compound images formed with 1 , 3 , 5 , 10 , and 50 angled plane - wave images .
lateral resolution was the worst for n = 1 , because no angle compounding takes place under this condition .
resolution improved with compounding , but was relatively unchanged as the number of coherent additions was increased .
this is expected because lateral resolution is dependent only on the maximum angle range of 10 , which is held constant for n > 1 .
signal - to - noise ratio ( snr ) and 12-db lateral beamwidth , mean standard deviation , of point spread function calculated from coherent compound plane - wave images of a 20-m diameter polypropylene thread produced from n subimages acquired at equal angular increments over 10 range
figure 2 shows compound coherent plane - wave images of the onh region obtained using 1 , 3 , 5 , 10 , and 50 plane - wave transmissions acquired over a 10 angle at a prf of 10 khz .
an improvement in snr was evident as the number of plane - wave images per compound image was increased .
compound plane - wave images of the optic nerve head region of a 66-year - old male subject obtained with ( a ) 1 , ( b ) 3 , ( c ) 5 , ( d ) 10 , and ( e ) 50 plane - wave images coherently added to form the final image .
figure 3 shows b - mode images of a human eye obtained with a conventional 10-mhz , single - element , mechanically scanned transducer and with the 18-mhz linear array .
the linear - array image was generated by coherent compounding of 20 angled plane waves over a 10 range .
plane - wave images provided superior sensitivity , demonstrating vitreous inhomogeneities and improved anatomic depiction of the anterior segment , including the anterior chamber and cornea .
the detached posterior vitreous face appeared brighter using the single - element probe , possibly due to its scan geometry and axially symmetric focus .
comparative b - mode images of a 66-year - old male subject obtained with an ophthalmic b - scanner using a 10-mhz single - element probe ( a , b ) versus the 18-mhz linear array by coherent compounding of 20 angled plane - wave images over a 10 range ( c , d ) .
figure 4 shows real - time power and velocity doppler images of the onh region obtained with a 4-khz doppler prf .
we found detection of blood flow in the region of the onh ( central retinal artery and short posterior ciliary arteries ) and choroid to be easily accomplished . at a prf of 4 khz
real - time ( a ) power doppler and ( b ) velocity doppler images of the posterior pole region of a 66-year - old male subject obtained with a 4-khz doppler prf using the flash doppler technique .
b - mode grayscale images were generated by coherent compounding of seven angled plane - wave images over a 10 range .
figure 5 shows compound plane - wave and power doppler images of the onh region obtained from two sets of data .
the figures clearly depict choroidal perfusion over the entire region being imaged and also flow in the central retinal artery and short posterior ciliary arteries . at a 6.66-khz prf
choroidal flow velocities , however , are slower than this , and power doppler is in any case unaffected by aliasing .
a temporal series of images obtained from the sliding window analysis demonstrates flow variation over the cardiac cycle ( movie clip s1 ) .
figure 6 shows flow - speed variation as a function of time in the choroid , central retinal vein ( crv ) , spca , and distal spca .
results show aliasing in the distal spca where the speed is greater than 14 cm / s .
table 3 summarizes repeatability of flow measurements of the spca over four scan sets of one subject .
average compound plane - wave images ( a , b ) , and power doppler images ( c , d ) of the onh region obtained from two sets of data from a healthy 46-year - old female subject . each set was acquired for 1.6 seconds at 6.66-khz compound imaging frame rate ( three angles over 10 per image ) .
after postprocessing with the plane - wave doppler technique , choroidal perfusion and flow in the short posterior ciliary artery and central retinal vein are visualized .
spectrograms of ( 1 ) choroid , ( 2 ) central retinal vein ( 3 ) , short posterior ciliary artery , and ( 4 ) distal short posterior ciliary artery depict flow velocity variation as a function of time .
aliasing is evident in the distal short posterior ciliary artery where the flow speed is higher than 14 cm / s .
mean , standard deviation , and coefficient of variation of the peak systolic velocity , end diastolic velocity , and resistive index of the short posterior ciliary artery calculated from four scans of one eye
in this report , we demonstrate ultrahigh - speed ultrasound imaging of the eye at a frame rate of up to 20,000 hz . as each image consists of 128 vectors ( i.e. , a - scans ) ,
the maximum imaging speed may be expressed as 2.56 mhz in a - scans / s , comparable to the speed of advanced ultrahigh - speed swept - source optical coherence tomography ( oct ) systems . indeed , there are many methodologic parallels between the ultrasound methods described in this report and oct angiography , which , like plane - wave ultrasound , requires high - speed acquisition of successive b - scans to demonstrate flow .
while the superior resolution attainable by oct makes it the optimal modality for imaging of the retina , the better penetration of ultrasound is advantageous for evaluation of optically occult anatomy and pathologies , including the orbit , choroid , ciliary body , tumors , and saccade - induced vitreous motion .
the first method is a real - time method that interleaves compound plane - wave depiction of anatomy with color - flow doppler derived from multicycle plane - wave transmissions emitted from a single angle .
because color - flow doppler utilizes a narrowband emission from just a single transmit angle , color - flow resolution is dependent on the angle of plane - wave transmission and does not benefit from the improved snr and lateral resolution of multiangle compounding .
the second method involves postprocessing of blocks of multiangle plane - wave data acquired continuously for greater than 1 second .
this method is particularly useful for depiction of slow flow , and it offers improved spatial resolution and snr because of the multiangle compounding .
one drawback of the compounding approach is that several gigabytes of data need to be acquired and the current matlab - based postprocessing for production of blood flow images requires approximately 15 minutes to complete .
this time could be sped up significantly with the use of graphics processing units and algorithm optimization . in compound
coherent plane - wave imaging , there is no tradeoff between frame rate and the size of the color - flow box because the entire medium is insonified with each transmission .
flow velocity estimation is obtained simultaneously for all image pixels , leading to full two - dimensional doppler flow imaging .
power doppler is advantageous in situations of slow flow in small tortuous vessels such as in the choroid .
power doppler encodes an estimate of the integrated doppler power spectrum rather than frequency shift ( which encodes velocity ) , so that power doppler intensity at each pixel position is a function of the amount of moving blood at that location .
high - resolution , power - doppler depiction of choroidal flow may thus offer a means for quantitative study of choroidal perfusion .
another advantage of this method is that it allows a spectral and temporal description of blood flow at any position over the whole image at any time point .
we showed that this technology can be used for the depiction and quantification of blood flow over a cardiac cycle in the orbital vessels and choroid .
the 6.66-khz prf ( of the compound image sequence ) we used for flow imaging was a good compromise between the detection of slow flow in the choroid and the depiction of high velocities in the central retinal vein and short posterior ciliary arteries ( albeit with aliasing ) .
working at a prf of 20 khz ( one angle ) , velocities up to 42 cm / s can be captured without aliasing , although resolution will be reduced . a lower prf , on the other hand ,
the choice of an 18-mhz probe was based on a tradeoff between resolution and attenuation , both of which increase with frequency . at 18 mhz , an axial resolution of approximately 80 m was obtained , and image quality was good to a tissue depth of at least 6 mm beyond the retina .
the methods described in this paper can readily be implemented using lower frequencies , which would enable visualization of retrobulbar flow to the orbital apex .
lower frequencies would also allow higher flow rates to be detected before encountering aliasing , but would degrade resolution .
conversely , higher frequencies would enable improved resolution and allow for imaging of flow in the anterior segment .
increased snr , combined with ultrafast real - time imaging , would be particularly useful for visualization of faint reflectors within the vitreous ( floaters ) during voluntary saccades to evaluate organization and possible vitreoretinal traction .
also , the presence of vitreous floaters has been shown to correlate with contrast sensitivity .
while the emphasis of this report is on b - mode and blood flow imaging using the plane - wave technique , this method can also capture other transient motions .
, for instance , studied saccade - induced vitreous velocity fields as a potential means for assessing risk of retinal tears .
they used a 20-mhz mechanically scanned transducer acquiring 20 images per second , which could be dramatically improved upon by plane - wave methods .
tanter et al . described use of plane waves to capture shear waves to characterize elasticity in ex vivo enucleated porcine corneas , and toubol et al .
ultrafast imaging might also allow assessment of vessel wall motions over the cardiac cycle , providing information about vessel wall rigidity .
the ultrahigh - speed technique could also be invaluable for study of ex vivo ocular deformation in blunt force trauma .
most significantly in terms of clinical application , plane - wave technology produces far lower acoustic intensity than conventionally scanned arrays , which will allow fda - compliant instrumentation for ocular blood flow imaging . while plane - wave array technology is certainly more complex than single - element mechanical b - scanners , given its benefits in speed , blood flow depiction , and safety , we can reasonably expect that commercial systems can be manufactured at prices comparable to oct systems , making clinical translation a feasible prospect .
the introduction of this technology into ophthalmology will open a new avenue toward investigation of hemodynamics in glaucoma and other ocular pathologies . | purposeophthalmic ultrasound imaging is currently performed with mechanically scanned single - element probes .
these probes have limited capabilities overall and lack the ability to image blood flow .
linear - array systems are able to detect blood flow , but these systems exceed ophthalmic acoustic intensity safety guidelines . our aim was to implement and evaluate a new linear - array based technology , compound coherent plane - wave ultrasound , which offers ultrafast imaging and depiction of blood flow at safe acoustic intensity levels.methodswe compared acoustic intensity generated by a 128-element , 18-mhz linear array operated in conventionally focused and plane - wave modes and characterized signal - to - noise ratio ( snr ) and lateral resolution .
we developed plane - wave b - mode , real - time color - flow , and high - resolution depiction of slow flow in postprocessed data collected continuously at a rate of 20,000 frames / s .
we acquired in vivo images of the posterior pole of the eye by compounding plane - wave images acquired over 10 and produced images depicting orbital and choroidal blood flow.resultswith the array operated conventionally , doppler modes exceeded food and drug administration safety guidelines , but plane - wave modalities were well within guidelines .
plane - wave data allowed generation of high - quality compound b - mode images , with snr increasing with the number of compounded frames .
real - time color - flow doppler readily visualized orbital blood flow .
postprocessing of continuously acquired data blocks of 1.6-second duration allowed high - resolution depiction of orbital and choroidal flow over the cardiac cycle.conclusionsnewly developed high - frequency linear arrays in combination with plane - wave techniques present opportunities for the evaluation of ocular anatomy and blood flow , as well as visualization and analysis of other transient phenomena such as vessel wall motion over the cardiac cycle and saccade - induced vitreous motion . | Methods
Ultrasound Intensity Determination
Resolution and SNR
Ultrafast B-Mode Imaging
Flash Doppler Imaging
Plane-Wave Doppler Imaging
Clinical Imaging Setup
Results
Ultrasound Intensity Determination
Resolution and SNR
Ultrafast B-Mode Imaging
Flash Doppler Imaging
Plane-Wave Doppler Imaging
Discussion
Supplementary Material |
pseudoaneurysms of the axillary artery are uncommon and usually encountered after penetrating or blunt trauma to the axilla ( 1 ) . in the case of blunt trauma
there tends to be an associated bony injury to the shoulder and most often an anterior dislocation ( 2 ) , in which axillary artery damage has been reported at around 0.3% prevalence ( 3 ) .
other injuries that have been described are fractures of the neck of the humerus and proximal humerus ( 4 ) .
the usual presenting complaint is a mass near the site of the trauma that is pulsating , painful , and warm .
indeed clinical suspicion can be lessened by the absence of hard initial signs of arterial injury ( 6 ) and the patient may present much later with potentially irreversible sequelae , particularly brachial plexus injuries ( 5 ) . here
we describe a unique case , where the patient presented without typical features of pseudoaneurysm and no dislocation or fracture and indeed the full consequences of the injury only became apparent when significant secondary neurological deficit had occurred .
a 30 year old patient presented to our institute after six months of an injury sustained to his left shoulder during a fall from a tree with complaints of progressively growing mass in left axillary region and gradual progression of neurological deficit to the point at which the arm became useless and insensate . on examination
1 ) . clinical photograph of pseudoaneurysm of left axillary artery the left radial , ulnar and brachial pulses were palpable but decreased as compared to the right side .
subsequent doppler study to look for vascular compression revealed pseudoaneurysm of axillary artery , which was confirmed by ct angiography ( fig .
ct angiographic cut showing pseudoaneurysm 3d reconstruction of ct angiogram showing displacement of vessel and leakage of blood into pseudoaneurysmal sac the patient was taken up for surgical management .
exploration was done and the proximal and the distal part of the axillary artery were controlled with umbilical tape and brachial plexus cords were identified and preserved . after administering 1 cc heparin ( 5,000 iu ) intravenously , we clamped the proximal and distal vascular structures and opened the capsule of the pseudoaneurysm with a direct incision .
the capsule was dissected and evaluated histopathologically and microbiologically . in order to avoid increasing the risk of major hemorrhage or nerve injury , we did not resect the aneurysmal pouch completely .
saphenous vein graft interpositioning was then performed because vascular structure was not conducive to end - to - end anastomosis .
there had been no recovery of neurological function in the arm at two months follow up .
aneurysms at less common locations are generally due to major trauma , syphilis , marfan syndrome , or infection .
atherosclerotic aneurysms are often seen in large arteries and in patients of advanced age , but pseudoaneurysms due to penetrating or blunt trauma are seen in patients of every age and at any location ( 7 ) .
frequency of pseudoaneurysms in the upper extremities is much lower than that in the lower extremities .
however , as lifespans increase and diagnostic and evaluation processes improve , the detection of such pseudoaneurysms is becoming more common .
infection , polyarteritis nodosa , congenital arterial defects , and especially trauma play a role in the pathogenesis of upper extremity pseudoaneurysms .
if the only causal factor is trauma , the aneurysm takes the form of a pseudoaneurysm .
sometimes , as in our report , patients are admitted to hospitals with pseudoaneurysms months or years after the trauma ( 7,8 ) .
pseudoaneurysms typically present as a mass near the site of the trauma that is pulsating , painful , and warm . since this patient presented late and without any typical features of pseudoaneurysm or evident bony injury , it was misdiagnosed as soft tissue tumor .
pseudoaneurysms after blunt trauma to the shoulder tend to occur in the third part of the axillary artery .
one theory for this is the lesser mobility of this region of artery because of the relatively fixed nature of the circumflex humeral and subscapular arteries , leading to tearing of the axillary artery with attempts at mobilisation ( 3,4 ) .
pseudoaneurysms of axillary artery are very rare in absence of bony injury in blunt trauma ( 9 ) . in our case patient
this has been described by several authors and can occur as a primary injury or delayed , as the aneurysm grows in size and compresses the plexus ( 10 ) .
delay in decompression is of paramount importance for recovery ( 1 ) . in this case decompression
two months post surgery , assessment by the rehabilitation team had not shown any sign of recovery .
the poor outlook is supported by several authors , including robbs et al ( 5 ) , who reported 12 cases of delayed ( after one to six weeks ) compression of the brachial plexus by an axillary pseudoaneurysm in a variety of injuries .
the outcome of the six patients presenting initially with total brachial plexus lesions were that none recovered fully and one showed no recovery whatsoever at 18 months .
the lesion was repaired by open surgical approach so as to remove organised thrombus , which was causing compression of the neurovascular bundle of arm .
an endovascular approach with insertion of a covered stent is a less invasive option for early cases of pseudoaneurysms . | traumatic pseudoaneurysm of the axillary artery is a rare sequela of injury to shoulder region .
we report here a unique case of delayed presentation of axillary artery pseudoaneurysm after a blunt injury , clinically mimicking soft tissue tumor without evidence of gross bony injury .
the gentleman presented after six months of injury with a progressively growing mass in left axillary region and neurological deficit .
ultimate management of the lesion was surgical resection and saphenous vein graft interpositioning .
unfortunately the lack of subsequent neurological recovery parallels some of the findings in the literature , from cases where decompression of the brachial plexus was not undertaken soon enough . | INTRODUCTION
CASE REPORT
DISCUSSION |
primary effusion lymphoma ( pel ) is a subset of non - hodgkin 's lymphoma ( nhl ) and was first described in 1989 .
this entity was noted in human immunodeficiency virus ( hiv ) patients , especially after nhl in patients with hiv had been determined to be an aids - defining illness .
a malignant lymphoblastic effusion when associated with human herpes virus 8 ( hhv-8 ) infections is defined as pel .
most of these affected patients are also coinfected with epstein - barr virus ( ebv ) .
hhv-8 is endemic in sub - saharan africa and the mediterranean region of the world .
latency - associated nuclear antigen-1 ( lana-1 ) is a gene product of hhv-8 , which is essential for viral dna maintenance during replication .
this protein binds to the p53 and retinoblastoma genes and inhibits tumor suppression by impairing apoptosis .
pel cells exhibit markers characteristic of plasma cells ( cd138 ) and lymphocyte activation ( cd30 , cd38 , cd71 and hla - dr ) but typical b cell and t cell markers are absent ( cd19 , cd20 , cd79a , cd3 , cd4 and cd8 ) [ 6 , 7 ] . however , no chromosomal abnormalities in terms of translocations and abnormal chromosomal numbers have been detected .
pel clinically manifests as a mass effect caused by the accumulation of fluid laden with malignant cells in body cavities . in the initial presentation , it is rarely detected beyond the pleural , pericardial and peritoneal surfaces .
extracavitary presentations have been reported , principally involving the gastrointestinal tract [ 9 , 10 ] . in this case report , we present the clinical course of pel in a patient with hiv who was found to have a right atrial mass in addition to pleural and pericardial effusions . this case is unique not only for its presentation as a right atrial mass but also for its favorable response to chemotherapy .
a 35-year - old hispanic male with aids without prior opportunistic infections who was recently started on antiretroviral therapy was referred from an outside hospital for the management of pericardial and bilateral pleural effusions .
one month earlier , he had presented to the same hospital with intermittent fevers , progressive weakness and 20-pound weight loss .
a computed tomography ( ct ) scan of the chest revealed a right atrial mass and mediastinal lymphadenopathy .
he was discharged home on bactrim , truvada , ritonavir and darunavir . during his second hospitalization
, he presented with syncope with no other localizing symptoms . on examination , he was in mild discomfort but otherwise afebrile and hemodynamically stable , with distant heart sounds and decreased air entry at the bases .
a ct scan showed mediastinal adenopathy , bilateral pleural effusions , a pericardial effusion and a right atrial mass ( fig .
a cardiac echocardiogram showed a right atrial mass and a large pericardial effusion with tamponade physiology ( fig .
fluid cytology showed large lymphoblastic cells with a positive immunohistochemistry staining for hhv-8 , cd30 and cd45 .
the biopsy of the right atrial mass via transvenous route showed large lymphoblastic cells with positive staining for hhv-8 , cd20 , cd30 and lambda light chains ( fig .
staining for cd138 , kappa light chain , pax5 , ebv , latent membrane protein 1 ( lmp1 ) , cd2 , cd3 , cd8 and cd56 was negative .
a diagnosis of pel with extracavitary involvement was made based on the presence of lymphoblastic cells and immunohistochemical staining .
the patient was continued on antiretroviral therapy , started on the r - epoch regimen as an inpatient and discharged home with outpatient follow - up appointments to oncology and infectious disease clinics .
subsequent imaging showed resolution of the pleural effusions and a significant decrease in the size of the right atrial mass ( fig .
effective treatment with highly active retroviral treatment has contributed to the decrease in the incidence of nhl .
very rarely , pel has been reported in patients with organ transplant recipients and chronic hepatitis c virus infection [ 11 , 12 , 13 ] .
it is a subtype of diffuse large b cell lymphoma with a unique constellation of clinical , morphologic , immunophenotypic and molecular characteristics .
there is no clear association with the cd4 count and viral load in hiv - infected patients [ 14 , 15 ] .
it predominantly affects males and is characterized by a symptomatic serous effusion with involvement of the pleura ( 6090% ) and pericardium ( 30% ) causing dyspnea , the peritoneum ( 3060% ) causing abdominal discomfort and distension , joint spaces causing joint swelling and , rarely , the meninges .
chest roentgenograms typically show pleural and pericardial thickening with an effusion in the absence of parenchymal abnormalities , masses or mediastinal enlargement [ 18 , 19 ] .
it rarely disseminates but can present as solid tumors involving the gastrointestinal tract , lymph nodes and bone marrow .
due to its unique liquid phase pattern of growth , fluid cytology is usually positive for malignant cells .
it is characterized by large multinucleated and multilobated cells with prominent nucleoli and abundant deep basophilic cytoplasm containing small clear vacuoles .
immunohistochemical staining is positive for plasma cell markers ( cd45 , cd30 , cd38 , cd71 , and cd138 ) but negative for b cell ( cd19 , cd20 and cd79a ) and t cell ( cd3 , cd4 and cd8 ) markers .
hhv-8 positivity ( lana-1 ) in the nuclei of malignant cells is important for clinching the diagnosis . despite frequent coinfection with ebv , staining for lmp1
there are no prospective trials and only a few retrospective treatment series are currently known .
the median survival without treatment is 23 months and increases to about 6 months with treatment .
different chemotherapy regimens have been used to treat this condition ( chop , hyper - cvad and rituximab ) [ 7 , 23 ] .
high - dose chemotherapy followed by hematopoietic stem cell transplantation has generated mixed results and these data are mostly from case reports [ 24 , 25 ] . in patients infected with hiv , a combination of antiretroviral therapy with chemotherapy has superior response than either modality used alone [ 14 , 23 ] .
radiation therapy can be used for palliation in patients who are not candidates for chemotherapy .
cytology and biopsy of the pericardial effusion and right atrial mass in our patient were positive for pel .
he had significant mediastinal lymphadenopathy and bilateral pleural effusions , which we thought were likely due to pel .
his mediastinal lymph nodes were not sampled and the pleural fluid was not sent for flow cytometry .
immunohistochemical staining of his right atrial mass biopsy was positive for hhv-8 and plasma cell markers ; however , the cells were positive for b ( cd20 ) and t ( cd4 ) cell markers as well . to our knowledge
, there has been only one case report of pel presenting as intracardiac mass , and the patient responded favorably to chemotherapy .
this is probably one of the few cases of pel with both cavitary and extracavitary involvements .
findings of an intracardiac mass in conjunction with pericardial and probably pleural and mediastinal lymph node involvement , cell markers positive for plasma cells , and b and t cells altogether make our patient a unique case of pel occurring in hiv infection . | primary effusion lymphoma ( pel ) is a subset of large b cell lymphomas and has been mostly associated with human immunodeficiency virus infection .
rare cases have been reported in organ transplant recipients and chronic hepatitis c patients .
it typically presents as an effusion in the pleural and pericardial spaces but rarely disseminates .
however , involvement of the gastrointestinal tract , lymph nodes and bone marrow has been reported .
diagnosis is based on characteristic clinical , histopathological and immunohistochemical features .
we present a case with a right atrial mass which tested positive for human herpes virus 8 ( hhv-8 ) , cd20 , cd30 and lambda light chains and negative for cd138 , kappa light chain , pax5 , epstein - barr virus , latent membrane protein 1 , cd2 , cd3 , cd8 and cd56 .
bilateral pleural effusions and pericardial effusions were noted which tested positive for hhv-8 , cd30 and cd45 .
the patient responded well to the r - epoch regimen with complete resolution of the effusions and a significant decrease in the size of the right atrial mass .
this case report illustrates the atypical manifestation of pel as a right atrial mass . | Introduction
Case Presentation
Discussion
Disclosure Statement |
a recent epidemiological study of intraocular inflammation in japan reported that sarcoidosis is the most prevalent uveitis.1 however , many of the cases do not meet the diagnostic criteria of sarcoidosis because of lack of systemic signs.2,3 we report two cases of ocular inflammation whose vitreous cytology supported the diagnosis of sarcoidosis .
a 56-year - old man was referred to our hospital with blurred vision in his right eye in april 2008 . on initial examination ,
the anterior chamber was mildly inflamed , but dense vitreous opacities were present in his right eye and optic neuritis was present bilaterally ( figure 1a and b ) .
fluorescein angiography showed dye leakage from both optic discs ( figure 1c and d ) .
the results of laboratory examinations were essentially normal , including serum levels of angiotensin - converting enzyme , calcium , gammaglobulin , anti - human t lymphotropic virus-1 antibody , anti - herpes simplex virus antibody , and anti - varicella zoster virus antibody .
examinations according to the criteria for sarcoidosis were negative and tuberculosis was ruled out by our department of internal medicine .
his visual acuity had decreased to 20/100 od , with increased numerous snowball - like vitreous opacities , and mutton - fat keratic precipitates and nodules were observed in the anterior chamber angles .
therefore , he underwent pars plana vitrectomy with a 25 gauge system to remove the dense vitreous opacities , and diluted and undiluted vitreous was obtained to determine the cause of the inflammation .
histiocytes , and epithelioid and multinucleated giant cells were detected by cytology in diluted vitreous samples , but necrotic materials and malignant cells were not detected ( figure 2 ) .
he received systemic corticosteroid therapy , and 2 months after surgery , optic neuritis was reduced and his corrected visual acuity had improved to 20/20 od .
a 77-year - old man was referred to our hospital with blurred vision in may 2009 .
he was diagnosed with lung small cell carcinoma in october 2008 , and received chemotherapy from december 2008 at our department of internal medicine . on initial examination ,
the anterior chamber was not inflamed , but numerous snowball - like vitreous opacities , optic neuritis , and periphlebitis were observed in both eyes ( figure 3a and b ) .
fluorescein angiography showed dye leakage from the optic discs and along the retinal veins in both eyes ( figure 3c and d ) .
neuron - specific enolase , progastrin - releasing peptide , and markers of lung small cell carcinoma were normal in the serum .
a computed tomography scan of the chest showed that the original focus of the lung small cell carcinoma had disappeared after chemotherapy .
examinations according to the criteria of sarcoidosis were negative , and tuberculosis was ruled out , as in case 1 .
the vitreous opacities in both eyes had increased a month later , and his corrected visual acuity was reduced to 6/20 od and 6/10 os .
the histological finding of sarcoidosis is a noncaseating granuloma consisting of epithelioid and multinucleated giant cells by biopsy.2 however , a biopsy of intraocular tissues is generally not performed because of the risk of visual complications.4 in addition , the intraocular tissues obtained are usually very small which makes it difficult to examine them by histological sections .
we collected all of the diluted vitreous during pars plana vitrectomy and submitted it for cytological analysis .
undiluted vitreous with high viscosity is not effective for collecting cells by cytospin , but diluted vitreous with low viscosity was effective .
this may be the reason why we detected epithelioid and multinucleated giant cells , although a previous report had failed to find these cells.5 we found that surgical removal of the vitreous was effective in restoring visual acuity , and vitreous cytology can be useful to support the diagnosis of sarcoidosis in patients whose eyes are considered to have sarcoidosis but systemic findings do not satisfy the diagnostic criteria . | the purpose of this paper is to report two cases of sarcoidosis with conflicting signs in which vitreous cytology was useful for supporting the diagnosis .
case 1 was a 56-year - old man who was referred with blurred vision , and was found to have iridocyclitis , vitreous opacities , and optic neuritis bilaterally .
he also had a swelling of both mandibular glands .
he received pulsed corticosteroid therapy , but the vitreous opacities and papilledema did not resolve .
the second case was a 77-year - old man referred with blurred vision , and both eyes had snowball - like vitreous opacities and optic neuritis .
the ocular findings in both cases strongly suggested sarcoidosis , but the systemic findings did not meet the diagnostic criteria for sarcoidosis .
we performed pars plana vitrectomy to remove the vitreous opacities , and the collected vitreous samples were sent for cytological analyses .
epithelioid and multinucleated giant cells pathognomonic of sarcoidosis were found in the vitreous samples which enabled us to make a diagnosis of sarcoidosis .
vitreous cytology can help in supporting a diagnosis of sarcoidosis , especially in cases of ocular inflammation suggesting sarcoidosis but systemic findings that do not satisfy the diagnostic criteria for this disease . | Introduction
Case report 1
Case report 2
Discussion |
it is not uncommon to encounter patients in critical care unit who develop sudden problem with ventilation while on mechanical ventilation .
causes may vary from patient related to ventilator related notably poor pulmonary compliance , increased airway resistance , and problem with ventilator , circuit or its settings . to manage the patient in this scenario where the ventilator is unable to deliver predetermined tidal volume
failing to appropriately recognize the underlying issue may lead to inappropriate management and its consequences .
a 40-year - old female admitted with complaint of shortness of breath for last 2 - 3 day , associated with cough and sputum streaking with blood for last around 15 days .
she had pulmonary tuberculosis in the past and had destroyed lung on the right side with mediastinal shift [ figure 1 ] . on the left side , she was having pulmonary infiltrates , for which she was receiving antibiotics .
her condition further deteriorated to the point that the patient was intubated with an endotracheal tube ( ett ) number eight and mechanically ventilated with sedation and paralysis .
mediastinal shift with tracheal deviation after a few hours of mechanical ventilation , her saturation began to drop , and blood pressure increased to more than 200 mmhg systolic with tachycardia . on realizing the problem that tidal volume
however , it was found that the suction catheter could not be passed as an obstruction was encountered .
on removing the tube , there was no blockage in the tube but now patient was reintubated with a seven number ett .
this was followed by delivery of set tidal volume and normalization of oxygen saturation and blood pressure . further into the patient 's management , after a few hours , patient developed the same problem of worsening oxygen saturation with rise in blood pressure and tachycardia .
again , the delivered tidal volume was not adequate and less than the predetermined value .
on looking specifically at airway pressure alarm limit nothing relevant found which could be the reason for failure to deliver predetermined tidal volume .
now , it was suspected that there could be impingement of ett bevel on the tracheal wall after intubation due to the anatomical distortion of trachea .
gradual withdrawal of the ett tip up to just below the vocal cords did not restore the ventilation .
in neonates , the distal orifice of an uncuffed ett abuts the tracheal wall and causes frequent obstruction . but for the adults , a cuffed ett does not allow free movements of the ett in the trachea and obstruction does not occur as often .
head movement shifts the secured ett within the trachea . yet for adults , anatomical deviations from normal seem to cause malposition or difficulty in ventilation .
they also did several manipulation to overcome the problem including withdrawing of tube as we did but to no avail .
the most likely reason of persisting problem in our patient was right - sided mediastinal shift which was creating an angle in tracheal anatomy in such a way that left - sided bevel was abutting tracheal wall .
we suspected this on the basis of not able to negotiate the catheter and left - sided bevel in a patient with right mediastinal shift . furthermore , there was no other apparent cause and problem was overcome by cutting bevel of tube .
reported a case of tube orifice abutting on the tracheal wall in a patient with forestier 's disease - diffuse idiopathic skeletal hyperostosis .
tracheal deviation due to destroyed lung may cause this problem due to tube tip abutting tracheal wall . | a 40-year - old female presented with respiratory difficulty , cough and sputum with blood streaking .
her right lung was destroyed , and trachea was shifted to the same side . on mechanical ventilation , she developed hypoxia and rise in blood pressure .
ventilator was not delivering set tidal volume . after looking into the cause
, it was decided to reintubate the patient with new endotracheal tube after cutting bevel .
thereafter , there was successful ventilation . | Introduction
Case Report
Discussion
Conclusion |
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