Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
starvation and other altered metabolic conditions such as immobilization , denervation ,
 aging , and unloading states induces loss of muscle mass1,2,3,4 . to study the signal
 transduction of atrophy in particular ,
various cell culture models have been developed5,6,7 . in many studies , exogenous cytokines such
 as tnf-
, glucocorticoids such as dexamethasone , and serum - free starvation of cultured cells
 have been used as atrophy models to confirm the mechanisms of whole skeletal muscle atrophy
 in vivo8,9,10 .
the elevated degradation of proteins in
 skeletal muscle atrophy and serum - free starvation is commonly coupled with activation of the
 protein ligases such as muscle specific ring finger-1 ( murf-1 ) and atrogin-11 , 4 , 5 , 11
.
 meanwhile , cofilin is a ubiquitously expressed protein in mammalian cells and thereby
 regulates the actin filament dynamics and reorganization and other functions12,13,14 .
furthermore , cofilin binds to actin
 molecules , changing fibrous actin to globular actin13 .
this process is enabled by the dephosphorylation of cofilin by
 phosphatases12 , 15 . on the other hand , phosphorylation of cofilin
abolishes the
 cofilin activity and inhibits its severing function12 , 16 ( fig . 1cfig .
1.change in phosphorylation of protein and schematic representation of the cellular
 response caused by serum - free starvation with low glucose .
morphologic ( a - a30 ,
 a - b100 ) and immunoblotting ( b ) analyses in the starved l6 myoblasts .
fbs , fetal
 bovine serum ; h , hours ; e. period , experimental period ; hg , high - concentration
 glucose ; lg , low - concentration glucose ; p - cofilin , phosphorylated cofilin ; r ,
 receptor ; f - actin , fibrous actin ; g - actin , globular actin ; rho - rac - cdc42 , rho family
 small gtpases ; rock , rho - associated protein kinase ; pak , p21-activated protein kinase ;
 ssh , cofilin - specific phosphatases slingshot ; skeletal mcs , skeletal muscle cells . ) .
however , the changes in phosphorylation of cofilin in starvation - induced atrophy
 are not fully understood .
therefore , we investigated the changes in the phosphorylation of
 cofilin in l6 myoblasts during serum - free starvation with low glucose
. change in phosphorylation of protein and schematic representation of the cellular
 response caused by serum - free starvation with low glucose .
morphologic ( a - a30 ,
 a - b100 ) and immunoblotting ( b ) analyses in the starved l6 myoblasts .
fbs , fetal
 bovine serum ; h , hours ; e. period , experimental period ; hg , high - concentration
 glucose ; lg , low - concentration glucose ; p - cofilin , phosphorylated cofilin ; r ,
 receptor ; f - actin , fibrous actin ; g - actin , globular actin ; rho - rac - cdc42 , rho family
 small gtpases ; rock , rho - associated protein kinase ; pak , p21-activated protein kinase ;
 ssh , cofilin - specific phosphatases slingshot ; skeletal mcs , skeletal muscle cells .
l6 myoblasts from rat neonate skeletal muscle were separated into control and serum - free
 starvation groups1 .
the control group of
 l6 myoblasts was purchased from the american type culture collection ( rockville , md , usa )
 and cultured in dulbecco s modified eagle s medium containing 10% fetal bovine serum , 100
 u / ml penicillin , 100  g / ml streptomycin , 200  mm glutamine , and 4,500  mg / l high - concentration
 d - glucose .
the serum - free starvation group of l6 myoblasts grown to 6070% confluence and
 undernourished in dmem containing 1,000  mg / l low - concentration d - glucose without fbs for 3 ,
 6 , 12 , 24 , 48 , and 72 h , respectively1 .

after each experimental treatment , cells were lysed with an extraction buffer ( 20  mm hepes ,
 ph 7.5 , 1% nonidet p-40 , 150  mm nacl , 10% glycerol , 10  mm naf , 1  mm
 na3vo4 , 2.5  mm 4-nitrophenylphosphate , 0.5  mm pmsf , and one tablet
 of complete proteinase inhibitor cocktail [ roche , indianapolis , in , usa ] ) .
the morphological
 changes in l6 myoblasts with or without each experimental treatment were visualized with an
 inverted microscope ( ae30/31 , motic incorporation , richmond , bc , canada ) . to measure the
 phosphorylation of cofilin
proteins ( 3045 g / lane ) were
 separated on 12% polyacrylamide sodium dodecyl sulfate gels and then transferred
 electrophoretically to a polyvinylidene fluoride membrane ( millipore ; bedford , ma , usa)2 .
anti - cofilin antibody was purchased from
 santa cruz biotechnology ( santa cruz , ca , usa ) .
antibody - specific bands were quantified
 using an image analyzer ( bio - rad ) .
the protocol for the study was approved by the committee
 of ethics in research of the university of yongin , in accordance with the terms of
 resolution 5 - 1 - 20 , december 2006 .
the data were
 statistically evaluated using student s t - tests for comparisons between pairs of groups and
 by anova for multiple comparisons . a p value of < 0.05 was considered to be statistically
 significant .
l6 cell sizes and numbers were diminished as a result of serum - free starvation in a
 time - dependent manner ( fig .
phosphorylation
 of cofilin was significantly decreased after 3 , 6 , 12 , 24 , 48 , and 72 hours of starvation
 compared with those of the control groups ( n=34 , fig .
 1b , table 1table 1.changes in expression and phosphorylation of cofilin of l6 myoblasts during
 serum - free starvation with low glucoseexperimental periodcofilin ( % ) p - cofilin ( % ) 0 hour ( control)100.00.0100.00.03 hours252.329.5 * 20.76.1 * 6 hours242.720.7 * 25.34.6 * 12 hours201.026.2 * 24.76.3 * 24 hours198.722.9 * 26.35.9
* 48 hours196.022.1 * 24.35.4 * 72 hours176.314.4 * 18.05.5*data were presented as the mean  sem .
the basal levels of
 abundance and phosphorylation in controls ( 0 hour ) were considered to be 100% .
 * compared with the 0 hour control , p<0.05 . ) .
however , the expression of cofilin was significantly increased after 3 , 6 ,
 12 , 24 , 48 , and 72 hours of starvation compared with the expression of cofilin in the
 control groups ( n=34 , fig .
p , phosphorylated protein . the basal levels of
 abundance and phosphorylation in controls ( 0 hour ) were considered to be 100% .
 * compared with the 0 hour control , p<0.05 .
skeletal muscle atrophy and joint contracture have proven to be significant orthopaedic
 problems in the area of physical therapy3 , 17 , 18 .
the skeletal muscle is the largest organ with high plasticity in the
 human , comprising about 50% of the total body weight .
maintenance of muscle mass and
 neuromuscular function is important for activities daily living ( adl ) in patients1 , 2 , 19 , and maintenance of muscle mass in
 particular is related in part to optimal nutrient absorption and use . in contrast , nutrient
 starvation and disuse have in part the potential to negatively impact muscle mass such as
 through skeletal muscle atrophy20,21,22,23 .
our previous study reported that the
 ubiquitin protein ligases murf-11 and
 atrogin-1 ( data not shown ) , markers of muscle atrophy , are increased in atrophied
 gastrocnemius muscle strips and involved in the development of serum - free starvation - induced
 atrophy in l6 myoblasts . simultaneously , extracellular signal - regulated kinase 1/2 ( erk1/2 ) ,
 stress - activated protein kinase / c - jun nh2-terminal kinase
 ( sapk / jnk ) , and p38 mitogen - activated protein kinase ( p38mapk ) are involved in atrophy
 caused by cast immobilization of a hind limb and serum - free starvation of l6 myoblasts1 , 2 .

also , our previous report demonstrated that cast immobilization of rat gastrocnemius muscles
 increases the expression of tissue myoglobin24 .
meanwhile , cofilin in eukaryotic cells binds to actin and plays a
 role in actin dynamics and reorganization involved in cast immobilization - induced
 atrophy14 , 25 .
phosphorylation of cofilin is achieved by lim kinases and thereby
 inhibits the actin binding , severing , and depolymerizing activities of cofilin16 , 25
 ( fig .
furthermore , the kinases responsible
 for this phosphorylation are rho - associated protein kinase and p21-activated protein kinase ,
 which are downstream kinases of the rho family small gtpases26,27,28 . on the other hand , dephosphorylation of cofilin
is mediated by the
 cofilin - specific phosphatases slingshot12 , 15 ( fig .

although cofilin is essential for maintenance of skeletal muscle mass12 , it has not been reported that
 phosphorylation of cofilin is related to atrophy caused by serum - free starvation in the area
 of physical therapy . however , further systematic studies in the area of physical therapy
 such as electrotherapy , neurotherapy , hydrotherapy , and others are needed to confirm the
 mechanism of cofilin under atrophic conditions29,30,31 ( fig .
in summary ,
 the phosphorylation of cofilin was decreased in starved skeletal muscle cells .
the present
 results suggest that serum - free starvation - induced atrophy may be in part mediated by
 cofilin from l6 myoblasts .

Answer:
[ purpose ] many studies have been using cell culture models of muscle cells with exogenous
 cytokines or glucocorticoids to mimic atrophy in in vivo and in vitro tests .
 however , the
 changes in the phosphorylation of atrophy - related cofilin are still poorly understood in
 starved skeletal muscle cells . in this study
 , we first examined whether or not
 phosphorylation of cofilin is altered in l6 myoblasts after 3 , 6 , 12 , 24 , 48 , and 72 hours
 of serum - free starvation with low glucose . [ methods ] we used western blotting to exam
 protein expression and phosphorylation in atrophied l6 myoblasts .
 [ results ] l6 cell sizes
 and numbers were diminished as a result of serum - free starvation in a time - dependent
 manner .
 serum - free starvation for 3 , 6 , 12 , 24 , 48 , and 72 hours significantly decreased
 the phosphorylation of cofilin , respectively .
 [ conclusion ] these results suggest that
 starvation - induced atrophy may be in part related to changes in the phosphorylation of
 cofilin in l6 myoblasts .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the truth is that most medical breakthroughs have ultimately come from basic research , and i think that we as scientists need to do a better job of telling these success stories .
my favorite example is that antibiotics came out of finding a random contaminant on a plate . and remember that we have crispr [ clustered regularly interspaced short palindromic repeats ] tools only because people were studying some bizarro antipathogen mechanism in bacteria .
it s a beautiful example of something entirely unanticipated coming out of left field . that s why it s important to maintain funding for a very diverse program of basic research ; history tells us you ca nt predict where the next advance will come from .
right now it seems like funding agencies and the public have an engineering mentality , and they believe that , as long as we think hard enough about a problem , we can solve it .
that s an admirable attitude , but in the life sciences it s not always the right path to discovery .
i would argue that under some circumstances , studying yeast cells is a better idea than studying highly transformed human cells in a dish .
for many years , we used to write in the  significance  section of grant applications that the reason that it is important to understand chromosome segregation is because , when it fails , cells become aneuploid and cancerous .
why should aneuploidy cause cells to proliferate ? when you do yeast crosses and by chance get an aneuploid strain , invariably the cells do poorly . and
one explanation is that building an organism is a complicated procedure , so if you change the gene dosage of certain genes , you mess everything up . that s probably true
you could then further argue that , at the cellular level , maybe it does nt really matter how many chromosomes you have , as long as you have at least one of each .
perhaps extra chromosomes are actually good for an individual cell and allow it to keep proliferating when they should not and this gives you cancer .
however , we never thought this was very likely , given that aneuploid yeast often proliferate poorly .
you can very agnostically ask : what happens to a cell if you change the chromosome number ?
yeast was the right organism for this because we have genetic tricks and selection methods to generate aneuploids that are stable enough to study .
because this allowed us to examine many different types of aneuploidies at the same time , we could look for broad patterns
. we could nt have done it in any other organism . actually , we do all our discovery work in yeast . and when we find something interesting , we move it into the mouse or human cell lines and ask whether we see the same thing .
sometimes the answer is  no ,  but more often the answer is  yes .
 it s just harder to discover fundamentally new things in very complex organisms where the repertoire of tools is limited .
and i would argue that , under some circumstances , studying yeast cells is a better idea than studying highly transformed human cells in a dish .
angelika amon s work over the past 15 years has guided all of us who think about mitotic and meiotic cell division .
, we wondered whether there was a systematic way the cell avoids losing or gaining chromosomes . to be honest
, i was hoping there would be some kind of cute mechanism that counts chromosomes . that turned out to be completely wrong . or at least we havent been able to find anything of this sort .
once we realized that , we had to step back and let the genetics lead the way .
we did a lot of phenotypic characterization and then developed hypotheses to explain the patterns we saw .
if complex subunits are not expressed in the correct ratios , often unassembled subunits need chaperones to maintain their soluble state and eventually need to be degraded if they can not find a binding partner .
cancer cells do nt only lose or gain whole chromosomes , they also have translocations and deletions and point mutations . we know that making and repairing dna requires a lot of nifty multi - subunit complexes ,
so our hypothesis was that whole - chromosome abnormalities cause stoichiometric imbalances in these complexes and this leads to defects in their formation and function .
so we re testing the idea that aneuploidy contributes to cancer because it s a mutator , rather than because it s a promoter of growth and proliferation , and we re doing more and more mouse work to answer those kinds of questions .
but we still use yeast to discover new properties of aneuploidy and to look at the cellular effects of changing the dosage of specific genes .
we started a new project on mitochondria a few years ago that i m really excited about .
one big question is : how did these two organisms start talking to each other ? did one learn english or the other learn french ? or did they resort to a more primitive sign language  metabolites  to talk to each other ?
the other thing i m fascinated by is that a large fraction of uncharacterized yeast genes localize to mitochondria .
that tells you there s a lot of biology in the mitochondria still to be learned .
what i think is even more important is that many of these genes are not at all conserved , not even in fungi .
so here are all these very new , very fast - evolving genes and nobody knows what they do !
usually when people hear that a gene is not conserved , they run !  arrgh !
it s something yeast specific !  but in this particular instance i think it s important and suggests mitochondria are still battling it out with the nucleus .
one way to look at it is to say the nucleus and mitochondria are not really symbiotic .
if mitochondria do nt get anything out of the relationship , they are really just slaves to the nucleus .
so the mitochondria are trying to escape the reign of the nucleus and the nucleus is fighting back in an arms race . and
if we can understand what all these nonconserved mitochondrial genes are doing , we can begin to find the frictions that still exist between the interests of the nucleus and the mitochondria .
i m totally fascinated by understanding how these different entities interact with each other inside a single cell .

Answer:
the genetics society of america medal is awarded to an individual for outstanding contributions to the field of genetics in the past 15 years .
 recipients of the gsa medal are recognized for elegant and highly meaningful contributions to modern genetics .
 the 2014 recipient , angelika b. amon , has uncovered key principles governing the cell cycle and was the first to demonstrate a connection between the physical completion of anaphase and the initiation of mitotic exit .
 more recently , her research has focused on the consequences of aneuploidy .
 genetics spoke with dr .
 amon about her approach to science and what is next on the horizon .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
cavernous hemangioma is a benign vascular malformation and belongs to a wide and continuous overlapping spectrum of hamartomas .
most cavernous haemangiomas occur in the vertebral body and may extend into the epidural space .
purely extradural cavernous hemangiomas without any vertebral body involvement is extremely rare and accounts for only 4% of all extradural spinal tumors and 12% of haemangiomas occurring extradurally .
we herein present a rare case of extradural dumbbell lumbar ( l3 ) cavernous hemangioma with paraspinal extension .
a 52-year - old female presented with insidious onset progressive low backache with pain radiating to whole of left lower limb associated with paraesthesias for two months .
left lower limb power was 4/5 in hip flexion , extension , abduction and adduction , 4/5 in knee flexion and extension , subtle weakness in ankle flexion and extension and great toe extension with hypotonia .
the reflexes of left lower limb were sluggish whereas on right side they were brisk ( normal ) . sensory examination
revealed impairment of all the modalities of sensations ( pin prick , touch , temperature , vibration- impaired upto anterior superior iliac spine ) from l2 to s4 dermatomes on left side .
magnetic resonance imaging of lumbar spine revealed an irregularly shaped , well defined extradural lesion at l3 vertebral level indenting the body , displacing the thecal sac posterolaterally and extending into left paraspinal region through l3- 4 neural foramen .
lesion was isointense on t1w , hyperintense on t2w images with strong homogenous enhancement on gadolinium contrast study [ figure 1 ] .
provisional preoperative diagnosis of schwannoma was considered . though the clinical findings and radiology were not concordant ,
the patient was suggested surgical intervention for the presence of enhancing mass lesion noted on the imaging with guarded prognosis .
shows irregularly shaped well defined extradural lesion ( arrows ) , hypointense on t1w ( a ) , hyperintense on t2w ( b ) images with homogenous contrast enhancement ( c , d , e ) and paraspinal transforaminal extension ( d , e ) the patient underwent left hemilaminectomy from l2 to l4 .
there was an extradural , brownish red , highly vascular mass located anterolateral to thecal sac at l3 vertebral body with well defined capsule around it .
left l3 nerve root was pushed superiorly by the tumor and it was not arising from any neural tissue .
it was dissected clear from the l3 nerve and the dura keeping the dissection over the coagulated capsule .
the spinal component of the lesion was excised in toto until the neural foramen , where it was coagulated and was cut sharply leaving behind the extra - foraminal portion .
microscopic examination revealed numerous dilated vascular channels of variable sizes lined by a single layer of flattened epithelial cells and filled with blood elements .
interspersed thick hyalinised blood vessels and mature adipose tissues were noted [ figure 2 ] .
radiotherapy was administered to the residual paraspinal portion of tumor [ figure 3 ] . for radiotherapy ,
the patient was immobilised in a vacuum locking device and ct simulation was done in the treatment position .
margin of 1 cm was added to the post contrast t1w mri to obtain the clinical target volume ; planning target volume was obtained by adding a margin of 0.5 cm to the clinical target volume .
three dimensional conformal radiotherapy was planned on eclipse planning system ( varian medical systems , palo alto , ca ) on linear accelerator ( clinac ix- 3665 ) using 6 mv x rays .
the dose prescription was 40 gy , 2 gy per fraction , 20 fractions given five days a week over five weeks .
( a , b ) the proliferating and anatomizing capillary channels lined by endothelial cells ( h and e , 100 ) shows postoperative changes ( arrow ) in spinal canal and residual tumor in paraspinal region
cavernous hemangioma is a benign vascular malformation , also known as cavernous malformation , cavernous angioma or cavernoma .
the cavernous hemangiomas occur throughout the neuroaxis including both intracranial and spinal compartments . according to location ,
its incidence in supratentorial , infratentorial and spinal compartments is 80% , 15% and 5% respectively .
purely extradural spinal cavernous hemangiomas are rare and the extension through intervertebral foramen into extraspinal region ( dumbbell ) is still rarer . in that case , it can be confused with commonly diagnosed nerve sheath tumors .
the onset of symptoms in these spinal cavernomas may be acute , progressive or remittent , depending on the biological behavior of the tumor .
lumbar extradural hemangiomas behave differently , not only from intramedullary cavernous hemangiomas but also from extradural cavernomas of other spinal locations .
purely extradural hemangiomas should be included in the differential diagnosis of lumbar extradural soft - tissue lesions .
in contrast to intracerebral cavernous hemangiomas , the patterns of density on ct scans and signal intensity on mr images are more homogenous in extradural hemangiomas .
another point of differentiation is the absence of low signal rim ( hemosiderin ) which is usually seen in intraaxial spinal cord cavernomas . as seen in present case , extradural cavernous hemangiomas
are usually isointense on t1w and hyperintense on t2w images and show homogenous contrast enhancement because of the presence of sinusoidal channels .
the lesion should be differentiated from other epidural neoplastic or inflammatory conditions , such as meningioma , neurofibroma , lymphoma , hemorrhagic vascular mass , granuloma and angiolipoma .
complete and in toto excision of the lesion should be attempted for clinical improvement ; however , in case of subtotal excision , adjuvant radiotherapy is advised .
radiosurgery as primary or adjuvant therapy is increasingly becoming an option as advances in radiosurgical equipment are enabling safe and accurate targeting of lesions .
though purely extradural cavernomas are rare in occurrence , they should be considered as possible differential diagnosis of dumbbell lesions of spine in view of operative nuances ( especially massive haemorrhage ) and management thereof .

Answer:
a 52-year - old female presented with slowly progressive left lower limb polyradiculopathy .
 mri of the lumbar region revealed an extradural dumbbell mass at l3 vertebral level , isointense on t1w and hyperintense on t2w images with homogenous contrast enhancement and extending into paraspinal region through left l3/4 foramen .
 l2 to l 4 left hemilaminectomy and excision of intraspinal part of tumor was performed .
 histopathological examination revealed presence of cavernous hemangioma .
 this case is reported because of its rarity , unusual dumbbell shape of lesion and difficulty in making a preoperative diagnosis without a coexisting bone lesion .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the diagnosis of rabies is not very difficult when associated with the classical features of excitations or phobias ( aerophobia , hydrophobia ) .
but it can be quite challenging when presented as acute flaccid paralysis ( afp ) .
we report here two cases of paralytic rabies who received four doses of postexposure ( grade iii dog bite ) vaccination without rabies immunoglobulin .
paralytic rabies occurring after postexposure antirabies vaccination creates a diagnostic dilemma as vaccine - induced gbs becomes a distinct possibility .
a ten year - old boy presented with sudden weakness of both lower limbs for two days .
he also had a history of fever , vomiting , and back pain for three days .
his past history elicited an incident of an unprovoked bite by a street dog in his right hand ( grade iii ) three weeks back .
four doses of purified chick embryo cell ( pcec ) antirabies vaccine were administered according to schedule in the deltoid , starting from the day of the bite .
the patient had complained of back pain , but there was no typical history of pain , tingling , numbness at the site of the bite , hydrophobia , or behavioral changes .
his temperature was 39.5c , pulse rate was 110/min , blood pressure 100/70 mm hg , respiratory rate 30/min , and spo2 96% . neurological examination detected grossly reduced muscle tone and power ( lower limb 2/5 , upper limb 3/5 ) with areflexia ( both superficial and deep tendon reflexes were absent ) in all four limbs and the trunk along with urinary incontinence .
the failure to administer rig after the grade iii bite favored a provisional diagnosis of paralytic rabies was made even though the classical symptoms of rabies were absent .
although rare with the modern cell culture vaccines , the possibility of vaccine - induced gbs was also considered .
laboratory investigations showed hemoglobin : 11.5 g / dl , white cell count : 70000/cu.mm ( neutrophil : 58% , lymphocyte : 40% , eosinophil : 2% ) , platelet count : 1,90000/cu.mm .
cerebrospinal fluid analysis showed cell count : 10/cu.mm ( all lymphocytes ) , protein : 50 mg / dl , and sugar : 80 mg / dl ( no albumino - cytological dissociation ) .
the electrophysiological test designed to identify features of demyelination ( slowing of nerve conduction velocity with marked prolongation of distal latencies and occasional conduction block ) , was inconclusive .
serum electrolytes were normal  na : 136 meq / l , k : 5 meq / l .
liver function , renal function tests , and repeat csf examination on the 7 day were unremarkable .
conservative management was started but rapid progression of paralysis occurred over the next two days .
intravenous immunoglobulin ( 2 g / kg / total dose ) was given over 12 hours for the sake of caution , but there was no improvement and the patient succumbed on the 10 day of onset of the disease .
due to inadequate stool collection by the afp surveillance worker , all the documents were sent to the national expert committee ( national polio surveillance project ) as a special case .
they classified the case as being nonpolio and as paralytic rabies . a six year - old girl presented with sudden onset of quadriparesis for one day , preceded by fever , myalgia , and vomiting for four days .
there was also a history of a dog bite in her right upper arm ( grade iii bite ) three weeks back .
the child was given the pcec vaccine as per schedule in the deltoid and received a total of four doses before the development of any symptoms .
the patient was treated conservatively , but the clinical features and the progression of disease was similar to the first case , except for the presence of myoedema , a striking feature of rabies . in spite of good supportive measures , she expired on the 12 day of disease onset .
results of laboratory investigations on the 11 day of the illness were also quite similar to the first case .
neutralizing antibodies to rabies virus were detected in both serum and csf by the rapid fluorescent focus inhibition test ( rffit ) .
a ten year - old boy presented with sudden weakness of both lower limbs for two days .
he also had a history of fever , vomiting , and back pain for three days .
his past history elicited an incident of an unprovoked bite by a street dog in his right hand ( grade iii ) three weeks back .
four doses of purified chick embryo cell ( pcec ) antirabies vaccine were administered according to schedule in the deltoid , starting from the day of the bite .
the patient had complained of back pain , but there was no typical history of pain , tingling , numbness at the site of the bite , hydrophobia , or behavioral changes .
his temperature was 39.5c , pulse rate was 110/min , blood pressure 100/70 mm hg , respiratory rate 30/min , and spo2 96% . neurological examination detected grossly reduced muscle tone and power ( lower limb 2/5 , upper limb 3/5 ) with areflexia ( both superficial and deep tendon reflexes were absent ) in all four limbs and the trunk along with urinary incontinence .
the failure to administer rig after the grade iii bite favored a provisional diagnosis of paralytic rabies was made even though the classical symptoms of rabies were absent .
although rare with the modern cell culture vaccines , the possibility of vaccine - induced gbs was also considered .
laboratory investigations showed hemoglobin : 11.5 g / dl , white cell count : 70000/cu.mm ( neutrophil : 58% , lymphocyte : 40% , eosinophil : 2% ) , platelet count : 1,90000/cu.mm .
cerebrospinal fluid analysis showed cell count : 10/cu.mm ( all lymphocytes ) , protein : 50 mg / dl , and sugar : 80 mg / dl ( no albumino - cytological dissociation ) .
the electrophysiological test designed to identify features of demyelination ( slowing of nerve conduction velocity with marked prolongation of distal latencies and occasional conduction block ) , was inconclusive .
serum electrolytes were normal  na : 136 meq / l , k : 5 meq / l .
liver function , renal function tests , and repeat csf examination on the 7 day were unremarkable .
conservative management was started but rapid progression of paralysis occurred over the next two days .
intravenous immunoglobulin ( 2 g / kg / total dose ) was given over 12 hours for the sake of caution , but there was no improvement and the patient succumbed on the 10 day of onset of the disease .
due to inadequate stool collection by the afp surveillance worker , all the documents were sent to the national expert committee ( national polio surveillance project ) as a special case .
a six year - old girl presented with sudden onset of quadriparesis for one day , preceded by fever , myalgia , and vomiting for four days .
there was also a history of a dog bite in her right upper arm ( grade iii bite ) three weeks back .
the child was given the pcec vaccine as per schedule in the deltoid and received a total of four doses before the development of any symptoms .
the patient was treated conservatively , but the clinical features and the progression of disease was similar to the first case , except for the presence of myoedema , a striking feature of rabies . in spite of good supportive measures , she expired on the 12 day of disease onset .
results of laboratory investigations on the 11 day of the illness were also quite similar to the first case .
neutralizing antibodies to rabies virus were detected in both serum and csf by the rapid fluorescent focus inhibition test ( rffit ) .
there are two forms of human rabies : i ) the well - known encephalitic ( furious ) and ii ) the paralytic ( dumb ) rabies .
the encephalitic form starts with fever , malaise , pharyngitis , and paraesthesia at the site of the bite followed by the classical neurological symptoms of hydrophobia , aerophobia , agitation , hypersalivation , and seizures .
this is followed by paralysis and coma ; death is usually due to respiratory failure .
the second clinical form of rabies , paralytic ( dumb ) or guillain - barr - like , is characterized by progressive paralysis without an initial furious phase . even though the paralytic rabies is unfamiliar to health care providers , 2030% of rabies victims present in this manner .
paralytic rabies is more common after rabid vampire bat bites and in persons who have received postexposure vaccination .
distinction of paralytic rabies from gbs may be difficult , although individuals with gbs usually do not have urinary incontinence , which is common in rabies . in our two cases ,
fever at the onset of disease , the absence of albumin - cytological dissociation , even repeat csf examination and persistent urinary incontinence was against the diagnosis of vaccine - induced gbs .
different sites of neural involvement and possibly different neuropathogenetic mechanisms may explain the clinical diversity in human rabies .
it is unclear whether weakness results from the involvement of anterior horn cells or of motor nerve fibers .
most likely , peripheral nerve dysfunction , due to demyelination , contributes to the weakness seen in paralytic rabies . on the other hand ,
progressive focal denervation starting at the bitten segment , was evident in furious rabies , even in the absence of demonstrable weakness .
intense inflammation of the spinal nerve roots was observed to a greater extent in paralytic rabies patients .
inflammation was mainly noted in the spinal cord segment corresponding to the bite in all cases .
however , central chromatolysis of the anterior horn cells could be demonstrated only in furious rabies patient . in both patients , ncv findings revealed features of demyelination which may occur in paralytic rabies as well as in gbs .
studies conducted in the us by the center for disease control and prevention ( cdc ) have documented that a regimen of one dose of rig and five doses of the human diploid cell culture vaccine ( hdcv ) over a period of 28 days was safe and induced an excellent antibody response in all recipients .
clinical trials with rabies vaccine adsorbed ( rva ) and purified chick embryo cell ( pcec ) vaccine have also demonstrated immunogenicity equivalent to that of hdcv .
many individuals did not receive immunoglobulin where indicated and some of them received the vaccine in the gluteal region instead of in the deltoid . although both of our patients had grade iii dog bite for which rig is strongly recommended , they only received the vaccine in the deltoid region without rig .
neurological reactions following newer vaccine administration have been extremely rare . after millions of vaccinations worldwide , three guillain - barr type paralytic reactions have been described , and all cases recovered completely . if our patients had vaccine - induced gbs , definitely they were improved by good supportive measures . during the early stages of paralytic rabies ,
notable signs include myoedema , particularly in the region of the chest , deltoid muscles , and thighs . however , this phenomenon , a brief , unpropagated , localized muscle contraction that appears in response to percussion with a tendon hammer , is not a confirmatory sign of paralytic rabies but was present in our 2 case .
if there is an inadequate stool sample with residual paralysis , death of the patient , or loss to follow - up at the time of afp surveillance , the case is referred to the national expert committee ( national polio surveillance project ) review for final classification as nonpolio afp or compatible with poliomyelitis . in our first case
, there was inadequate stool sampling , so it was reviewed by the expert committee and declared to be paralytic rabies .

Answer:
two clinical forms of rabies are recognize : i ) a furious form associated with classical signs of excitation or phobic symptoms , ii ) dumb rabies ( paralytic rabies ) characterized by progressive paralysis without an initial furious phase wherein distinction from guillain - barr syndrome may be difficult .
 paralytic rabies is more common in persons who have received postexposure vaccination .
 we report here the diagnostic dilemma of two cases of acute flaccid paralysis due to rabies .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
malignant melanoma is an aggressive skin cancer accounting for about 4.5% of all new cancer cases and 1.7% of all cancer deaths in the united states .
malignant melanoma can metastasize to various sites including , but not limited to , the brain , lung , and gastrointestinal tract .
intra - thoracic metastases in malignant melanoma most commonly present as multiple or solitary pulmonary nodules and rarely as isolated pleural effusions .
though there are few reported cases of recurrent malignant melanoma presenting with isolated pleural effusion , what makes our case intriguing , is its presentation in the context of coexisting chronic lymphocytic leukemia ( cll ) .
a 65-year - old caucasian woman presented in march 2007 with a 3-month history of painless left - sided cervical lymphadenopathy .
she denied any associated fevers , chills , loss of weight , dyspnea , dysphagia , or any other symptoms .
the patient 's surgical history was pertinent for a completely resected stage ia melanoma over the left shoulder 16 years before this presentation .
physical exam revealed enlarged and non - tender cervical and axillary lymph nodes without splenomegaly .
a complete blood picture showed a white blood cell count of 14.7  103/l , an absolute lymphocyte count of 7.35  103/l , hemoglobin of 13.8 g / dl , a platelet count of 258  103/l , and lactate dehydrogenase of 291 u / l .
flow cytometry of the peripheral blood demonstrated a monoclonal lymphocyte population expressing cd5 , cd19 , cd20 , cd24 , cd43 , and cd52 with lambda light chain restriction and no increase in cd34-positive blasts .
based on the above findings , the patient was diagnosed with rai stage i cll and placed under observation .
two years after her initial diagnosis , the patient presented with progressive dyspnea , associated with pleuritic chest pain and a 20 lbs weight loss over a period of 3 months .
physical examination revealed increased axillary and cervical lymphadenopathy and decreased breath sounds over the right lung .
white blood cell count was noted to be 53.4  103/l , and she had an absolute lymphocyte count of 40.7  103/l .
the pleural fluid analysis was consistent with an exudative effusion , with increased atypical lymphocytes .
the majority of the lymphocytes were cd4 + t - lymphocytes ( cd4:cd8 in a ratio of 15 : 1 ) , but polymerase chain reaction failed to show any clonal t - cell receptor- or t - cell receptor- gene rearrangements .
secondary to rapid reaccumulation of pleural fluid , increasing lymphadenopathy , and rapid doubling time of lymphocyte count , the decision to treat symptomatic cll was made .
chemotherapy with pentostatin , cyclophosphamide , and rituximab did not result in any meaningful clinical response .
as the patient 's pleural effusion was refractory to cll treatment , video - assisted thoracoscopic surgery was performed , which demonstrated diffuse nodular thickening of both visceral and parietal layers of the pleura ( fig .
a biopsy of these lesions revealed enlarged cells with an increased nuclear - cytoplasmic ratio and pleomorphic nuclei with occasional cherry red nucleoli ( fig .
electron microscopy revealed type ii melanosomes with cross - striated lattice in an enclosed membrane ( fig .
1e ) , type iii melanosomes with increased deposition of electron - dense melanin , and type iv melanosomes with highly electron - dense melanin ( fig .
computed tomography of the chest revealed extensive lobulated tumor lining the entirety of the right parietal pleural surface without any evidence of parenchymal involvement .
the patient 's medical condition rapidly declined , and she ultimately succumbed to death before initiation of any therapy .
cll is a low - grade lymphoproliferative state characterized by the accumulation of functionally incompetent monoclonal b - lymphocytes .
immunosuppression in cll is hypothesized to be a result of immunosuppressive factors released by the neoplastic b cells that downregulate t - cell function .
loss of  chain and costimulatory molecule cd28 on t - cell lymphocytes   along with reduced il-4 and ifn- expression by cd4 + t cells in patients with cll   also seem to play a role in the t - cell dysfunction in cll .
the immune system plays a crucial role in immunosurveillance against malignant transformation and tumor propagation   and , hence , t - cell dysregulation and dysfunction in cll patients increase their risk of recurrent or secondary malignancies . in several retrospective studies involving patients with cll ,
increased incidence of secondary cancers like kaposi sarcoma , head and neck cancer , lung cancer , and malignant melanoma was noted [ 7 , 8 ] .
reported that the overall risk of any second - incident cancer in cll patients was higher than in the general population ( second - incident cancer : 2.17 , 95% ci 2.072.27 ) , and the risk of melanoma was found to be 7.74 times that of the general population ( 95% ci 6.858.72 ) .
hence , prompt detection and treatment of the malignant melanoma are crucial in patients with cll .
metastases to various viscera have been known to occur even after the resection of the original tumor . however , isolated pleural metastasis with pleural effusion as a metastatic recurrence is very rare . in a series of 130 patients with malignant melanoma and thoracic complications ,
15% were found to have pleural effusions , and less than 3% had isolated and unilateral pleural effusion .
only a handful of cases with recurrent isolated metastatic pleural involvement presenting after a prolonged period after resection of the primary lesion were reported , with the longest reported progression - free survival being 14 years [ 12 , 13 ] . in our patient , isolated pleural metastases were noted 16 years from the complete resection of the skin lesion . computed tomography of the chest may aid in the diagnosis of pleural metastasis by demonstrating thickened pleura and parenchymal involvement .
positron emission tomography may also aid in the detection of fdg - avid pleural metastasis .
thoracentesis , unless contraindicated , should be considered in all cases of suspected malignant pleural effusions .
effusions in malignant melanoma are relatively richer in cd8 + than in cd4 + t - lymphocytes . in our case , the majority of the cells in the pleural effusion expressed cd4 + , and only 12% of the lymphocytes expressed the markers expressed by tumor cells .
the latter can be explained by the deficient migratory capacity of the b - cll cells , which might have led to a relative enrichment of reactive t cells .
video - assisted thoracoscopic surgery and pleural biopsy may be useful for diagnosis and to perform molecular studies .
concomitant history of cll , pleural fluid studies suggestive of cll , and a distant history of malignant melanoma made the diagnosis challenging in our patient .
we speculate that immune dysregulation associated with cll could have led to recurrence of melanoma in our case .
our case underlines the importance of having a suspicion for malignant melanoma in patients presenting with isolated pleural effusion , especially in the setting of an underlying lymphoproliferative disorder and a previous history of melanoma .

Answer:
isolated pleural metastasis with pleural effusion is a rare occurrence in malignant melanoma .
 we report an unusual case of a patient with chronic lymphocytic leukemia ( cll ) and recurrent pleural effusions .
 the pleural fluid cytology and immunohistochemistry profile were consistent with the diagnosis of cll . however
 , chemotherapy with pentostatin , cyclophosphamide , and rituximab did not result in any meaningful clinical response .
 a video - assisted thoracoscopic surgery and biopsy of the affected nodular parietal layer of the pleura were consistent with malignant melanoma .
 our case underlines the importance of having a suspicion for secondary causes of effusion in patients with cll .
 we briefly discuss the mechanisms of an increased incidence of secondary cancers in cll and the diagnosis of isolated pleural metastases in malignant melanoma .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
microleakage between the root canal filling and root - canal walls may adversely affects the results of root - canal treatment.1 apical leakage is considered to be common cause of endodontic failure.2 hence , different endodontic filling materials , sealers and techniques have been introduced to the dental community in an attempt to improve apical seal.1 various materials have been used in root canal treatment in an attempt to achieve success .
but , a combination of gutta - percha and a sealer are used most commonly .
gutta - percha is considered an impermeable core material ; therefore , leakage through an obturated root canal is expected to take place at the interfaces between the sealer and dentin or the sealer and gutta - percha , or through voids within the sealer.3 apical sealing is desirable to prevent passage of bacteria and their endodotoxin apically . in vitro evaluation of apical dye penetration
is used to estimate the sealing ability which is corresponding to in vivo amount of micro leakage with particular sealer.2 many techniques were used to evaluate the leakage of sealers such as ; colored dye penetration radio labeled tracer penetration dissolution of hard tissue clearing of teeth , spectrometry of radioisotopes electrochemical and gas chromatography .
however , many studies showed no significant difference between these techniques.1 the aim of this in vitro study was to quantitatively evaluate the sealing properties of three different root - canal sealers ; tubliseal , sealapex and ah26 using a spectrophotometric method .
thirty - six extracted sound mandibular molar natural teeth specimens with complete root and free from caries or cracks were collected , stored , disinfected and handled as per the recommendations and guidelines laid down by occupational safety and health administration and centers for disease control and prevention.4 the teeth were then placed in 0.9% physiologic saline solution for ten days prior to access cavity preparation .
the samples were divided into three experimental groups ; group i : sealapex , group ii : tubliseal and group iii : ah26 with 12 samples in each group .
the samples were then coated with nail varnish all over the root surface except 2 mm around the apical foramen . 2 ml of freshly prepared 2% methylene blue dye was taken in each vial and the apical third of the root was suspended in the dye for 72 h. samples were washed with distilled water , nail varnish removed and then placed in 20 ml of 35% nitric acid for 72 h. standard solutions of 1% , 0.5% , 0.2% , 0.05% , 0.02% and 0.01% of methylene blue in 35% nitric acid were prepared and stored for 72 h. the standard solutions and the nitric acid solutions were filtered and centrifuged for 1 min after 72 h. the supernatant was subjected to spectrophotometric analysis using a filter of 670 nm .
the amount of leakage was extrapolated from a standard linear regression curve constructed from stock standard methylene blue dye solutions .
obtained data were statistical analyzed with kruskal  wallis and mann  whitney u - tests using spss software version 20 ( ibm ) .
the results of the quantitative evaluation of the sealing properties of the three root - canal sealers are shown in table 1 .
, tubliseal showed a significant difference ( p > 0.005 ) . in comparison to sealapex
comparisons made between tubliseal and ah26 showed no significant difference ( table 2 , chart 1 ) . mean and standard deviation values of volumetric dye penetration in groups with reference to transmission .
three - dimensional obturation of the root canal system with a fluid impervious seal is an important factor for successful endodontic therapy .
the root canal filling should seal the canal both apically and coronally to prevent the passage of microorganism to apex or vice versa.5 most reliable method is the use of gutta - percha cones with sealer cement .
sealers based on zinc oxide - eugenol ( tubliseal ) , calcium hydroxide ( sealapex ) , epoxy resins ( ah26 ) were included in the present study . in present quantitative dye leakage study ,
tubliseal demonstrated least dye leakage in comparison with other experimental groups ( table 1 ) .
our results were in contrary to study by masoud and saleh where they found more microleakage in tubliseal group than other groups.6 sealapex is a calcium hydroxide type sealer .
calcium hydroxide used as root canal sealer since it stimulates periapical tissues in order to maintain health or promote healing and secondly for its antimicrobial effects.7 it has been observed in some studies that , calcium hydroxide sealers showed a significant volumetric expansion during setting because of water absorption , which increases its solubility .
the present in vitro investigation indicated maximum leakage value with sealapex among the experimental groups . in a contradictory to our results , cobankara et al .
( 2006 ) observed sealapex with better apical sealing than the other sealers ( ah plus and rc sealer ) at 7 , 14 , and 21 days.3 ah26 is an epoxy resin based sealer that provides easy handling characteristics , good flow , good sealing to dentin and prominent antimicrobial activity.6 kumar et al . observed more micro leakage with zinc oxide - based sealer and least with resin based sealers , this is contradictory to our study.8 in our study , there was no statistical significant difference between tubliseal and ah26 in micro leakage .
observed least amount of dye penetration for ah plus and endorez group.9 even though , the current study did not indicate any statistically significant difference between ah26 and sealapex , it is time to question the overall efficacy of calcium hydroxide sealers on the grounds that the reparative and the calcification capabilities attributed to calcium hydroxide are generally desirable before completing the obturation .
ah26 , resin based sealer provided a better apical seal when compared with sealapex even though the results were statistically not significant .
it mixes easily , flows well , and has ample working time , good radio - opacity , comparable solubility , good adhesion and good biocompatibility.3 in the present study , there was no significant difference between group ii and iii and group i and iii .
did nt find any significant difference between the tested three groups ; sealer 26 , enfoflas and resin group .
but they observed higher microleakage in sealer 26 group compared with control.11 joseph and sing evaluated the apical sealing with four root canal sealers ; ah26 , sealapex , endoflas fs and ah plus and observed no significant differences between all groups except between ah plus and endoflas.5 nagas et al .
observed significantly lower overall leakage with ah plus group , whereas no difference was found between master cone points.12 kopper et al . observed significant dye penetration for ah plus , endofill and sealer 26.13 cobankara et al .
observed better sealing values for roekoseal after 21 days when compared to ketac - endo and ah plus , and there was no statistically significant difference.1 dultra et al . found no statistical difference between groups for apical leakage ( endofill , ah plus , endorez and epiphany).14 in addition , before accepting a new material for routine clinical use further experiments
should also be performed to evaluate the other aspects of the materials physical and biological properties such as biocompatibility , solubility , disintegration , radio - opacity and dimensional stability . however
, these in vitro studies do provide comparative information of the relative performance of sealers tested under the same conditions in each particular study and clinicians can use this information to possibly choose a better sealer .
in the present study , tubliseal sealer showed least microleage compared with sealapex and ah26 sealer .
it is important to remember before declaring any root canal sealer as most acceptable that the results of the dye penetration studies indicate only the relative sealing ability of root canal fillings in vitro and they do not indicate their ability to prevent the penetration of bacteria into filled root canals in vivo .

Answer:
background : the aim of this study was to quantitatively analyze the amount of dye leakage with ah26 , sealapex and tubliseal sealers in endodonticaly treated teeth.materials and methods : a total of 36 extracted mandibular molar specimens were divided into three groups ; group i : sealapex , group ii : tubliseal , group ii : ah26 with 12 samples in each group .
 standard access cavity and biomechanical preparation was done with step back flare technique .
 obturations were done using respective sealers in the three different groups .
 then , samples were subjected to spectro photometric analysis using a filter of 670 nm .
 spectrophotometric analysis was performed to quantitatively analyze the amount of dye leakage with all three sealers.results:tubliseal exhibited the least microleakage . in comparison to sealapex
 , tubliseal showed a significant difference . compared to sealapex
 , ah26 showed no significant difference .
 comparisons made between tubliseal and ah26 showed no significant difference.conclusion:in the present study , tubliseal sealer showed least microleage compared with sealapex and ah26 sealer .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
while drugs can cause acute rhabdomyolysis individually , they can also interact with other drugs by cytochrome p450 and p - glycoprotein mechanisms to bring on the syndrome.clinicians should evaluate drug interactions in patients taking two or more medications .
acute rhabdomyolysis ( ar ) is a clinical syndrome that occurs when the electrolytes and myoglobin that are released upon skeletal muscle damage enter into the circulation system .
there are several ways in which ar may occur , one of which is drugs ( fig .
1etiology of acute rhabdomyolysis and its complications etiology of acute rhabdomyolysis and its complications a comprehensive study was carried out in 2011 using 20042009 data of the us food and drug administration ( fda ) to reveal which drugs may be associated with rhabdomyloysis .
the etiologies of 16,435 drug - induced cases of rhabdomyloysis involved hmg - coa reductase inhibitors or statins ( n  =  4325 , 26.3  % ) as the first suspect .
a total of 100 cases were reported for diclofenac and 99 for omeprazole , a proton pump inhibitor , while there were no reports of cases associated with pantoprazole .
the cases of drug - induced rhabdomyolysis in previous literature were also associated with statins , and the frequency is similar to that reported in the abovementioned report . that said , drug interactions could not be assessed because the fda data did not include that level of systematic information .
the gastric side effects of non - steroidal anti - inflammatory drugs ( nsaids ) are well known , and their concomitant or subsequent combination with proton pump inhibitors is common . a review of adverse drug reactions , creatinine kinase elevations , and muscle events , including muscle weakness , myopathy , myositis , and polymyositis , analyzed such multiple drug regimens and found that the addition of pantoprazole to a treatment regimen was the cause of all muscle events , aside from myalgia .
a 45-year - old man was referred to hospital complaining of fatigue and extensive body pain .
his medical history included stress - induced headaches that had been present for almost the entire previous year , for which he began using diclofenac at 50  mg / day as the frequency of headaches had increased during the prior month .
he was referred to a physician for pyrosis , 1  week prior to presenting at the hospital , and was prescribed pantoprazole at 40  mg / day .
he started to experience pain in his leg muscles on the fourth day of the diclofenac and pantoprazole combination regimen and used two 50-mg doses of diclofenac to control the pain .
the muscle pain became more widespread on the fifth day , and the patient also developed fatigue .
an examination revealed a blood pressure of 120/80  mmhg and a pulse of 76  bpm , full and rhythmic .
muscular strength was good ; however , the patient complained of muscle tenderness upon palpation .
neurological and general system examinations were normal ; no abnormal findings were seen in an electrocardiogram ; and an abdomen ultrasound revealed no pathology , aside from an abdominal gas distention . a laboratory analysis revealed high levels of muscle destruction products , the foremost of which was creatinine kinase ( table  1 ) .
glucose , urea , creatinine , cholesterol levels , amylase , direct and indirect bilirubin , electrolytes , anti - streptolysin o , c - reactive protein , rheumatoid factor , and thyroid hormones were all within their normal ranges.table  1laboratory parameters of patientadmission7  days afterreference rangeglucose ( mg / dl)96n / a70105alp ( alkaline phosphatase ) ( iu / l)565164306sgpt ( iu / l)4512042sgot ( iu / l)8814534ck ( iu / l)31146724190creatinine ( mg / dl)0.760.670.751.25crp ( mg / dl)0.880.5905ldh ( iu / l)230168125220
 alp alkaline phosphatase , ck creatine kinase , crp c - reactive protein , ldh lactate dehydrogenase , n / a not available , sgot serum glutamic oxaloacetic transaminase , sgpt serum glutamic pyruvic transaminase laboratory parameters of patient
 alp alkaline phosphatase , ck creatine kinase , crp c - reactive protein , ldh lactate dehydrogenase , n / a not available , sgot serum glutamic oxaloacetic transaminase , sgpt serum glutamic pyruvic transaminase a cardiac pathology was excluded because the electrocardiographic assessments and cardiac sounds were normal , and because the patient did not describe any pain that would indicate an infarct , and test results and findings were stable on the following days .
ar was considered as a pre - diagnosis , as there was a chronologic alignment between the patient s clinical representation and the medications he used , and this was supported by the laboratory parameters .
both medications were discontinued and the patient was followed up for 1  week , during which no medical interventions were carried out , aside from a recommendation of general hydration .
the ar diagnosis was confirmed because his complaints disappeared , with his laboratory values returning to the normal range , a stable electrocardiogram , and other systemic examinations being found within normal ranges .
to date , among the cases involving nsaids , two cases were reported that include diclofenac - induced rhabdomyloysis [ 4 , 5 ] . the patient detailed in this study was referred with extensive pain and fatigue , and represents the third case in which rhabdomyloysis developed while using 100-mg / day diclofenac tablets .
the other two cases were induced by diclofenac alone , with no interaction with other drugs . of these , one patient was admitted with pain that increased after the patient took 200  mg of diclofenac within 2  days ( 50  mg tablet / twice a day ) for joint pain .
the other case involved a patient who used diclofenac to ease an acute exacerbation of gout .
the patient was referred to a physician on the 13th day of intramuscularly self - administered diclofenac at 75  mg per day for 6  days , followed by 75  mg orally three times a day for 7  days . unlike the previous case , this patient was referred to the hospital because of erythematous pruritic eruptions that developed on various parts of his body . while drugs can cause ar individually , they can also interact with other drugs to bring on the syndrome .
the cyp1 , cyp2 , and cyp3 gene families are overall responsible for drug metabolism , and the similarities between the amino acid sequences within a gene family are at least 40  % , although the level of similarity may increase to 85  % between subgroups . the genetic polymorphisms in these genes
alter the biotransformation of the drug . while fast metabolizers have increased enzyme activity , slow metabolizers show decreased enzyme activity . among these genes ,
theophylline , which is metabolized through this pathway , when used with erythromycin , returns to the cyp1a2 pathway and can not reach toxic concentrations [ 79 ] .
that said , to date , no such theory has been put forward for diclofenac and pantoprazole in the cyp enzyme system .
the fact that they are metabolized through the same subgroup ( 2c ) can be associated with a possible drug interaction .
this possibility of interaction between diclofenac and pantoprazole has been investigated in a randomized crossover trial of 24 subjects , and the results showed that the peak plasma concentrations of diclofenac are sustained in a stable range , and that diclofenac does not affect the pharmacokinetics of pantoprazole , meaning that this combination is completely safe .
however , the results of an in - vitro study using diclofenac as a substrate marker for human liver microsomes suggested the contrary . according to this study , proton pump inhibitors , the strongest one being pantoprazole , carry a strong potential for drug interaction by inhibiting the activity of cyp enzymes , and it was underlined that drug interactions are significantly more pronounced in weak metabolizers with an enzyme deficiency .
p - glycoprotein ( p - gp ) is an adenosine triphosphate - dependent efflux transprotein that is found in the membranes of the enterocytes .
it is expressed by the mdr1 gene in humans and can be found in various organs , including the liver , kidneys , intestinal region , and blood  brain barrier .
p - gp actively pumps its substrates xenobiotics to the extracellular space and decreases their intracellular concentrations .
proton pump inhibitors , including pantoprazole , anti - arrythmic drugs , anticancer drugs , antibiotics , and antidepressant drugs , inhibit p - gp , and therefore the modulation of this pump plays a crucial role in drug  drug interactions [ 12 , 13 ] .
while drugs can cause ar individually , they can also interact with other drugs to bring on the syndrome .
the cyp1 , cyp2 , and cyp3 gene families are overall responsible for drug metabolism , and the similarities between the amino acid sequences within a gene family are at least 40  % , although the level of similarity may increase to 85  % between subgroups . the genetic polymorphisms in these genes
alter the biotransformation of the drug . while fast metabolizers have increased enzyme activity , slow metabolizers show decreased enzyme activity . among these genes ,
theophylline , which is metabolized through this pathway , when used with erythromycin , returns to the cyp1a2 pathway and can not reach toxic concentrations [ 79 ] .
that said , to date , no such theory has been put forward for diclofenac and pantoprazole in the cyp enzyme system .
the fact that they are metabolized through the same subgroup ( 2c ) can be associated with a possible drug interaction .
this possibility of interaction between diclofenac and pantoprazole has been investigated in a randomized crossover trial of 24 subjects , and the results showed that the peak plasma concentrations of diclofenac are sustained in a stable range , and that diclofenac does not affect the pharmacokinetics of pantoprazole , meaning that this combination is completely safe .
however , the results of an in - vitro study using diclofenac as a substrate marker for human liver microsomes suggested the contrary . according to this study , proton pump inhibitors , the strongest one being pantoprazole , carry a strong potential for drug interaction by inhibiting the activity of cyp enzymes , and it was underlined that drug interactions are significantly more pronounced in weak metabolizers with an enzyme deficiency .
p - glycoprotein ( p - gp ) is an adenosine triphosphate - dependent efflux transprotein that is found in the membranes of the enterocytes .
it is expressed by the mdr1 gene in humans and can be found in various organs , including the liver , kidneys , intestinal region , and blood  brain barrier .
p - gp actively pumps its substrates xenobiotics to the extracellular space and decreases their intracellular concentrations .
proton pump inhibitors , including pantoprazole , anti - arrythmic drugs , anticancer drugs , antibiotics , and antidepressant drugs , inhibit p - gp , and therefore the modulation of this pump plays a crucial role in drug  drug interactions [ 12 , 13 ] .
the fda recommends that clinicians check cyp - mediated potential drug interactions routinely . in this case report , a case of diclofenac- and pantoprazole - induced ar is evaluated for drug - interaction mechanisms , and different perspectives are presented . while evaluating the patients with side effects of drugs ,
the cyp and p - gp mechanisms that play roles in drug absorption and distribution should be considered .
written informed consent of the participant was obtained after the nature of the procedures had been fully explained .
the case report was carried out in agreement with the latest version of the declaration of helsinki .

Answer:
backgrounddrugs represent one of the etiologic causes of acute rhabdomyolysis ( ar ) with drug - induced rhabdomyolysis most commonly associated with hmg - coa reductase inhibitors .
 ar etiology can also result from the use of diclofenac , a non - steroidal anti - inflammatory drug , and omeprazole , a proton pump inhibitor .
 cases of ar triggered by pantoprazole have never before been reported , although it has been observed that its inclusion in multiple drug therapies can result in muscle events.case presentationa 45-year - old man presenting with complaints of fatigue and extensive body pain was diagnosed with acute rhabdomyolysis .
 his symptoms started on the fourth day of the concomitant use of diclofenac and pantoprazole .
 the patient was using diclofenac 50-mg tablets once daily for 1  month and pantoprazole 40-mg tablets once daily during the previous week for headaches and pyrosis , resulting in an increase in his creatinine kinase levels to 3114  iu / l ( reference range
 24190  iu / l ) on the fifth day of concomitant use .
 his creatinine kinase levels returned to normal and his complaints disappeared after the seventh day of discontinuation of both treatments.discussiona third case of diclofenac - induced rhabdomyolysis was defined in which , different from previous cases , ar was detected during the concomitant use of diclofenac and pantoprazole .
 the timing of the symptom development and the limited number of ar cases induced by diclofenac and pantoprazole suggested a drug interaction.conclusionthe close relationship between diclofenac and pantoprazole , and the cytochrome p450 and p - glycoprotein systems offers a strong indication that a drug interaction may be occurring .
 while evaluating the side effects of drugs in patients undergoing monotherapy , clinicians should also consider the mechanisms that play a part in drug absorption and distribution .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
the ewing sarcoma family of tumors , including ewing sarcoma and the more differentiated counterpart , primitive neuroectodermal tumor , are the second most common primary malignancies of bone in childhood and adolescence   but can also occur in the soft tissues .
systemic chemotherapy is aimed at treating known or micrometastatic disease as well as improving local control of the cancer .
the intergroup ewing sarcoma study ( int-0091 ) demonstrated that a regimen of alternating cycles of vincristine - doxorubicin - cyclophosphamide and ifosfamide - etoposide was superior to vincristine - doxorubicin - cyclophosphamide alone , leading to a 5-year event - free survival of 69% versus 54% in the standard arm .
more recently , a randomized trial evaluated dose intensification by interval compression ( administering cycles every 2 weeks ) and found that approach to be superior , with a 4-year event - free survival of 76% in the dose - dense arm compared with 65% in the standard 3-week chemotherapy arm .
this is now considered by pediatric oncologists to be the standard chemotherapy regimen for patients with ewing sarcoma , although it has not been adequately evaluated in patients older than 18 .
although there have been improvements in the outcome for patients with localized disease , the outcome for patients with metastatic disease and for those who relapse is poor , with survival rates of 20% for those with metastases   and 10 - 20% following a recurrence .
therefore , in addition to standard chemotherapeutics , future clinical trials will need to incorporate novel biologic agents in an effort to achieve further survival improvements .
the insulin - like growth factor ( igf ) system has two principal ligands : igf-1 and igf-2 .
these ligands mediate their stimulatory effects via the igf-1 receptor ( igf-1r ) , a transmembrane receptor tyrosine kinase . under normal physiologic circumstances , igf-1 and igf-2
are stimulated by growth hormone and function in a negative feedback loop to control growth hormone release .
the insulin growth factor - binding proteins ( igfbps ) regulate the available free igf proteins available for igf-1r activation [ 7 - 9 ] . upon ligand binding , autophosphorylation of the igf-1r tyrosine kinase initiates activation of the mitogen - activated protein kinase and phosphoinositide 3-kinase / akt pathways , leading to proliferation , survival [ 10 - 13 ] , and enhanced angiogenesis via downstream induction of vascular endothelial growth factor .
the igf-2 receptor is a monomeric transmembrane protein with no kinase activity and has not been shown to play a role in the development of ewing sarcoma .
the pathway also has a role in promoting neuronal survival , myelination , and postnatal mammary development and lactation .
in addition , metabolic pathways use the igf system to help integrate signals from nutrition and stress in order to shift appropriately between anabolic and catabolic states .
high circulating levels of igf-1 have been associated with the risk of developing prostate , breast , or colorectal cancer .
in addition , igf-1r expression is known to be necessary for cellular transformation and for signal transduction pathways stimulated by the igf-1r to enhance tumor cell growth and proliferation . furthermore
, igf-1r gene expression is regulated by a number of tumor suppressors , including wt1 , brca1 , and p53 .
there are also data to suggest that signaling through the igf-1r enhances resistance to cytotoxic chemotherapy .
therefore , inhibition of the igf-1r is a potentially important therapeutic target against a variety of tumors .
the insulin - like growth factor ( igf ) system has two principal ligands : igf-1 and igf-2 .
these ligands mediate their stimulatory effects via the igf-1 receptor ( igf-1r ) , a transmembrane receptor tyrosine kinase . under normal physiologic circumstances , igf-1 and igf-2
are stimulated by growth hormone and function in a negative feedback loop to control growth hormone release .
the insulin growth factor - binding proteins ( igfbps ) regulate the available free igf proteins available for igf-1r activation [ 7 - 9 ] . upon ligand
binding , autophosphorylation of the igf-1r tyrosine kinase initiates activation of the mitogen - activated protein kinase and phosphoinositide 3-kinase / akt pathways , leading to proliferation , survival [ 10 - 13 ] , and enhanced angiogenesis via downstream induction of vascular endothelial growth factor .
the igf-2 receptor is a monomeric transmembrane protein with no kinase activity and has not been shown to play a role in the development of ewing sarcoma .
the pathway also has a role in promoting neuronal survival , myelination , and postnatal mammary development and lactation .
in addition , metabolic pathways use the igf system to help integrate signals from nutrition and stress in order to shift appropriately between anabolic and catabolic states .
high circulating levels of igf-1 have been associated with the risk of developing prostate , breast , or colorectal cancer .
in addition , igf-1r expression is known to be necessary for cellular transformation and for signal transduction pathways stimulated by the igf-1r to enhance tumor cell growth and proliferation .
furthermore , igf-1r gene expression is regulated by a number of tumor suppressors , including wt1 , brca1 , and p53 .
there are also data to suggest that signaling through the igf-1r enhances resistance to cytotoxic chemotherapy .
therefore , inhibition of the igf-1r is a potentially important therapeutic target against a variety of tumors .
the igf signaling pathway and , in particular , the igf-1r play a major role in the development and proliferation of ewing sarcoma .
early studies documented the major autocrine role of the igf-1 and igf-1r pathways in ewing sarcoma , and expression of igf-1r has been shown to be a requirement for ews / fli-1 transformation in fibroblasts .
a variety of approaches in vitro and in animal models have been undertaken to disrupt the igf-1r signaling pathway , including the development of small - molecule tyrosine kinase inhibitors ( tkis ) and anti - igf-1r antibodies . in preclinical testing
, there was an initial difficulty in obtaining specific small - molecule kinase inhibitors of the igf-1r due to a very - high - sequence homology with kinase and atp - binding domains of the insulin receptor .
after initial attempts , the tki nvp - aew541 was shown to have a 27-fold increased selectivity for the igf-1r over the insulin receptor . this small - molecule tki has shown promise in preclinical models , where inhibition of migration , metastasis , and angiogenesis was seen in vitro and a significant reduction in tumor growth was seen in xenograft models .
further elucidation of the metabolic alterations related to the use of tkis will be necessary prior to entry into clinical trials .
more recently , targeted antibodies have been shown not only to disrupt ligand - receptor binding , but also to decrease surface igf-1r expression by internalization and degradation of the antibody - bound receptor .
human monoclonal anti - igf-1r antibodies have been produced by many pharmaceutical companies : imc - a12 ( imclone systems , new york , ny , usa ) , amg 479 ( amgen , thousand oaks , ca , usa ) , r1507 ( roche , basel , switzerland ) , cp-751,871 ( pfizer inc , new york , ny , usa ) , sch717454 ( schering - plough corporation , kenilworth , nj , usa ) , mk-0646 ( merck ) , and ave1642 ( immunogen , inc , waltham , ma , usa / sanofi - aventis , paris , france ) .
these antibodies have been tested in preclinical settings and ongoing early - phase adult studies [ 30,32 - 36 ] .
the sch717454 igf-1r antibody was tested against a panel of pediatric tumors by the pediatric preclinical testing program , a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models .
intermediate or high activity was demonstrated in two of five ewing sarcoma xenografts , including one complete response .
in addition , the imc - a12 antibody is currently under investigation in a phase ii children 's oncology group ( cog ) trial , with a stratum available for patients with ewing sarcoma . through the sarcoma alliance for research through collaboration ( sarc ) , the r1507 antibody has been tested in two phase i studies in adults .
the first study assessed the administration of the antibody on a 3-week basis and was well tolerated , without any dose - limiting toxicity or serious adverse events ; 11 of 26 patients were found to have stable disease , although none had ewing sarcoma . in the second study ,
four of eight heavily pretreated patients with ewing sarcoma demonstrated stable disease , with two of eight patients demonstrating durable partial responses .
the igf signaling pathway and , in particular , the igf-1r play a major role in the development and proliferation of ewing sarcoma .
early studies documented the major autocrine role of the igf-1 and igf-1r pathways in ewing sarcoma , and expression of igf-1r has been shown to be a requirement for ews / fli-1 transformation in fibroblasts .
a variety of approaches in vitro and in animal models have been undertaken to disrupt the igf-1r signaling pathway , including the development of small - molecule tyrosine kinase inhibitors ( tkis ) and anti - igf-1r antibodies . in preclinical testing
, there was an initial difficulty in obtaining specific small - molecule kinase inhibitors of the igf-1r due to a very - high - sequence homology with kinase and atp - binding domains of the insulin receptor .
after initial attempts , the tki nvp - aew541 was shown to have a 27-fold increased selectivity for the igf-1r over the insulin receptor . this small - molecule tki has shown promise in preclinical models , where inhibition of migration , metastasis , and angiogenesis was seen in vitro and a significant reduction in tumor growth was seen in xenograft models .
further elucidation of the metabolic alterations related to the use of tkis will be necessary prior to entry into clinical trials .
more recently , targeted antibodies have been shown not only to disrupt ligand - receptor binding , but also to decrease surface igf-1r expression by internalization and degradation of the antibody - bound receptor .
human monoclonal anti - igf-1r antibodies have been produced by many pharmaceutical companies : imc - a12 ( imclone systems , new york , ny , usa ) , amg 479 ( amgen , thousand oaks , ca , usa ) , r1507 ( roche , basel , switzerland ) , cp-751,871 ( pfizer inc , new york , ny , usa ) , sch717454 ( schering - plough corporation , kenilworth , nj , usa ) , mk-0646 ( merck ) , and ave1642 ( immunogen , inc , waltham , ma , usa / sanofi - aventis , paris , france ) .
these antibodies have been tested in preclinical settings and ongoing early - phase adult studies [ 30,32 - 36 ] .
the sch717454 igf-1r antibody was tested against a panel of pediatric tumors by the pediatric preclinical testing program , a comprehensive program to systematically evaluate new agents against childhood solid tumor and leukemia models .
intermediate or high activity was demonstrated in two of five ewing sarcoma xenografts , including one complete response .
in addition , the imc - a12 antibody is currently under investigation in a phase ii children 's oncology group ( cog ) trial , with a stratum available for patients with ewing sarcoma . through the sarcoma alliance for research through collaboration ( sarc ) , the r1507 antibody has been tested in two phase i studies in adults .
the first study assessed the administration of the antibody on a 3-week basis and was well tolerated , without any dose - limiting toxicity or serious adverse events ; 11 of 26 patients were found to have stable disease , although none had ewing sarcoma . in the second study ,
four of eight heavily pretreated patients with ewing sarcoma demonstrated stable disease , with two of eight patients demonstrating durable partial responses .
human monoclonal antibody therapy directed against the igf-1r holds great promise for improving the prognosis for children , adolescents , and adults with ewing sarcoma .
the recent data demonstrating responses in heavily pretreated patients with refractory ewing sarcoma bring a wave of excitement to move these therapies to the forefront .
clinical trials are under way to assess the feasibility and efficacy of combining anti - igf-1r therapy with multiagent chemotherapy . over the next 5 years
, feasibility testing will be completed , and if successful , phase iii studies will assess whether the addition of these new agents will result in therapeutic improvements .

Answer:
the insulin - like growth factor ( igf ) signal transduction pathway appears to play a key role in the development and proliferation of the ewing sarcoma family of tumors .
 integration of anti - igf-1 receptor therapy into the standard treatment for these patients is a novel approach that will likely be incorporated into future treatment to determine whether such agents will improve the outcome for patients with this malignancy .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
macrolide , lincosamide and streptogramin b ( mlsb ) antibiotics are structurally different with a same mechanism of action .
these drugs , especially clindamycin , are alternative drugs for some staphylococcus aureus infections such as skin and soft tissue infections particularly in penicillin - allergic patients ( 1 , 2 ) .
clindamycin resistance in s. aureus strains may be either constitutive ( cmlsb ) or inducible ( imlsb ) .
relapse of infection in a patient with s. aureus endocarditis was reported in 1976 ( 3 ) .
detection of isolates with inducible clindamycin resistance is a problematic issue for the routine diagnosis , because they are erythromycin resistant and clindamycin susceptible in vitro and in the condition that they are not place adjacent to each other . in these cases , in vivo treatment with clindamycin may lead to clinical therapeutic failures ( 4 , 5 ) .
the aim of this study was to determine the incidence of inducible clindamycin resistance in s. aureus isolates collected from clinical specimens in this geographic area .
totally 162 s. aureus isolates were collected from clinical specimens of patients admitted to three university hospitals with 462 , 420 and 300 bed capacities in kerman , south - east of iran , from march 2011 to february 2012 .
confirmation of s. aureus isolates and detection of methicillin resistant s. aureus ( mrsa ) were performed by phenotypic and genotypic methods as previously described ( 6 ) . only one isolate per patient
this test was performed by placing an erythromycin ( 15 g ) disk ( mast , group ltd .
, merseyside , uk ) at a distance of 15 to 20 mm from clindamycin ( 2 g ) disk ( mast , group ltd . ,
merseyside , uk ) on a mueller - hinton agar plate inoculated with 0.5 mcfarland standard bacterial suspensions . following overnight incubation at 37c , flattening of the clindamycin zone adjacent to the erythromycin disk ( d shaped ) indicated inducible clindamycin resistance ( 7 ) .
from 162 s. aureus isolates tested for determination of inducible clindamycin resistance , 70 ( 43.2% ) were mssa and 92 ( 56.8% ) isolates were mrsa ( table 1 ) .
sensitivity to both erythromycin and clindamycin was significantly higher in mrsa compared to mssa isolates .
resistance to methicillin , erythromycin and clindamycin was observed in 92 ( 56.8% ) , 75 ( 46.29% ) and 46 ( 28.4% ) of the isolates , respectively .
inducible resistance to clindamycin was determined in 14 ( 8.64% ) isolates ( d - test positive , figure 1 ) .
table 2 shows the distribution of d - test positive s. aureus isolates in clinical specimens . among those , 11 ( 78.57% )
abbreviations : mssa , methicillin susceptible s. aureus ; mrsa , methicillin resistant s. aureus ; ery , erythromycin ; cli , clindamycin ; s , sensitive , r , resistant ; cmlsb , constitutive macrolide lincosamide and streptogramin b ; imlsb , inducible macrolide lincosamide and streptogramin b. data are presented as no . ( % ) .
flattening of the clindamycin zone adjacent to the erythromycin disk produces a d shape .
( % ) .   including : blood , skin and soft tissue , cerebrospinal fluid .
clindamycin is an effective antibiotic agent used in the treatment of skin and soft - tissue infections caused by s. aureus isolates .
this antibiotic has good tissue penetration , potential antitoxin effects , and also accumulates in abscesses ( 8) .
however , resistance to clindamycin may develop in s. aureus isolates with inducible phenotype and these isolates have a high rate of spontaneous mutation which would enable these isolates to develop constitutive resistance to clindamycin during therapeutic process ( 4 ) . a positive
d - test indicates the existence of inducible resistance to clindamycin . in this study 8.64% of 162
s. aureus isolates were d - test positive that is comparable with the findings of the studies by rahbar and hajia ( 9.7% ) ( 9 ) and sedighi et al .
the prevalence of inducible and constitutive clindamycin resistance differs in different geographic areas ( 12 ) .   in our study
high number ( 46.29% ) of s. aureus isolates were resistant to erythromycin . among those , 14 ( 18.66% ) isolates had positive and 15 ( 20% ) had negative d - test results and 46 ( 61.33% ) were constitutive clindamycin resistance . in this study the prevalence of inducible and constitutive resistance to clindamycin in mrsa ( 11.95% and 47.8% respectively ) is higher than those in mssa ( 4.28% and 2.85% , respectively ) .
the results of this study revealed that inducible resistance to clindamycin in s. aureus isolates is relatively high in this region .
therefore , d - test should be performed to prevent treatment failures of s. aureus infections caused by the agents that are resistant to erythromycin and sensitive to clindamycin .

Answer:
background : clindamycin is a frequently used antimicrobial therapeutic medicine used for the treatment of skin and soft tissue infections caused by staphylococcus aureus strains . resistance to this antibiotic is either constitutive or inducible .
 constitutive resistance to clindamycin could be detected by standard susceptibility testing methods .
 inducible clindamycin resistance could not be detected by in vitro routine tests .
 this type of resistance can be identified by d-test.objectives:the outbreak of inducible resistance to clindamycin in methicillin resistant and - susceptible s. aureus isolates were investigated in this study.materials and methods : totally 162 s. aureus isolates were evaluated for inducible clindamycin resistance by d - test in accordance with clinical and laboratory standards institute ( clsi ) guidelines.results:inducible clindamycin resistance was detected in 8.64% of s. aureus isolates .
 inducible and constitutive resistance to clindamycin was found to be higher in methicillin resistant s. aureus ( 11.95% and 47.8% respectively ) compared to methicillin susceptible s. aureus ( 4.28% and 2.85% respectively ) isolates.conclusions:our results showed that inducible resistance to clindamycin in s. aureus isolates is relatively higher in this region .
 therefore , d - test should be performed to prevent treatment failures against infections caused by s. aureus , which are resistant to erythromycin and the sensitive ones against clindamycin .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
over the past few decades , the advancement in breast screening and management has increased the overall survival in women with breast cancer . but
this in turn , exposes them to the risk of developing new primary malignancies or metastases .
the metastatic involvement of gastrointestinal ( gi ) tract is rare and that of the rectum even rarer . even though lobular carcinoma constitutes only 10% of breast cancers , it is the commonest breast cancer metastasizing to the colon and rectum ( 1 ) .
these metastatic lesions can lead to diagnostic challenge for clinicians as they can mimic primary colo - rectal cancer due to the lack of diagnostic signs .
we report a rather unusual case of metastatic invasive ductal carcinoma masquerading as primary rectal cancer .
a 60 year old woman presented with a suspicious lump in her left breast in early 1996 and underwent open diagnostic surgical excision . she was found to have a moderately differentiated invasive ductal carcinoma measuring up to 20 mm in its greatest diameter extending less than 1 mm from the diagnostic excision margin . subsequently , she underwent left mastectomy and axillary node clearance which failed to show any residual invasive cancer . however , there was residual high grade cribriform dcis present adjacent to the diagnostic surgical excision cavity in the mastectomy specimen .
there was no evidence of vascular invasion and none of the seven lymph nodes excised contained any metastatic carcinoma [ g2t1n0mx ] .
since her cancer was oestrogen receptor ( er ) positive , she was started on tamoxifen post - operatively .
she presented 2 years later with localised pain in her right knee and bone scan revealed an isolated bony metastasis in the right proximal tibia .
this was managed using palliative radiotherapy to control the symptoms and her adjuvant hormonal therapy was switched to anastrazole ( astrazeneca plc , london , united kingdom ) .
she neither developed any loco - regional recurrence nor had any progression of her metastatic disease for the next 9 years . during this period
, she underwent annual mammographic and clinical follow - up with her adjuvant hormonal treatment being stopped in 2005 after clinical consultation . in early 2007 , she presented with ongoing history of fresh rectal bleeding , alternating bowel habit and mucus discharge per rectum .
abdomen was soft , non - tender without any organomegaly and digital rectal examination revealed a palpable tumour at 6 o'clock position .
fungating rectal tumour on colonoscopy she underwent colonoscopy , which revealed a fungating tumour at 10 cm from the anal verge in the rectum and rest of the colon was normal ( figure 1 ) .
the histopathological examination of the biopsy revealed a poorly differentiated invasive adenocarcinoma ( figure 2 ) .
tumour overlying the large bowel mucosa with the line demarcating the tumour edge with arrow pointing at the body of the tumour ( magnification4 ) .
considering her previous history of invasive breast cancer , pathologist performed immunohistochemistry of the colonic biopsies .
the tumour cells were strongly positive for cytokeratin ( ck ) 7 with focal positivity for er but were negative for both carcino embryonic antigen ( cea ) and ck 20 .
the above immunohistochemistry profile with previous history of breast cancer favoured a metastatic breast origin over a primary colonic cancer even though the clinical and colonoscopic findings were not typical .
the staging ct scan did nt show any evidence of metastasis and the mri scan revealed a locally advanced tumour with involvement of mesorectal facial margins with possible involvement of the peritoneum locally ( figure 3 ) . the bone scan failed to reveal any evidence of active metastatic disease . mri scan .
arrow pointing to the localized tumour in the rectum with no evidence of widespread metastasis after discussing in the multi - disciplinary team meeting ( mdt ) , it was decided to treat the tumour with a short course of pre - operative radiotherapy .
the histopathological examination of the resected tumour showed poorly differentiated metastatic adenocarcinoma with predominantly solid , but with focal glandular growth pattern and large areas of necrosis .
the tumour involved full thickness of the bowel but the serosal surface and the resection margins were free of cancer .
there was no evidence of metastatic cancer in any of the twenty two lymph nodes excised .
immunohistochemistry showed tumour cells to be negative for cea and ck 20 , but was strongly positive for ck7 ( figure 4 & 5 ) .
the tumour also showed focal positivity for er and was negative for both progesterone receptor ( pr ) and human epidermal growth factor receptor 2 ( her2 ) . after comparing the morphological and immunohistochemistry charachteristics of the primary breast cancer and rectal tumour
, the pathologist concluded that the features were consistent with a primary breast cancer metastasising to the rectum .
she underwent an uneventful post - operative recovery and remains disease free during her follow - up until now .
ck 20 immunohistochemistry positive normal large bowel mucosa with the adenocarcinoma being negative ( magnification  4 ) .
in the largest clinical series till date , only < 1% ( 17 out of 2604 patients followed over 18 years ) of the patients with breast cancer were found to have gastro - intestinal [ gi ] metastasis ( 2 ) .
information gathered from autopsy series shows small intestine being the commonest site of metastasis ( 28% ) followed by oesophagus ( 25% ) , stomach ( 25% ) , colon ( 19% ) and rectum ( 4% ) .
the commonest route of metastasis to the gi tract is through the haematogenous route followed by lymphatic and peritoneal spread .
even though there are a few case reports of lobular carcinoma metastasizing to the rectum , there are only 3 case reports in the literature of invasive ductal carcinoma metastasizing to the rectum till date ( 3 - 5 ) . as a clinician the main challenge lies in the differentiation of such metastatic lesions from primary colo - rectal cancer as
the clinical presentation of metastatic lesion can be non - specific and mimic a primary cancer as in the present case .
the radiological investigations like , ct scan and double contrast barium enema are helpful in localizing the lesion but can not differentiate between them .
on endoscopy , the colo - rectal metastasis appear as diffuse thickening of the colonic wall mimicking linitis plastica or like in crohn s disease with ulcerated or nodular areas rather than as a solitary , discrete mass seen in primary colonic lesion ( 1 ) .
but the differentiation was made more challenging in our case , as colonoscopy revealed a solitary fungating mass arising from the rectal mucosa mimicking a primary rectal cancer .
histopathological examination by itself may not be conclusive as the tumour invasion is primarily in the sub - serosa , so unless deep endoscopic biopsies are available the diagnosis will be made only after resection of the tumour .
but immunohistochemical markers such as er , pr , gross cystic disease fluid protein ( gcdfp-15 ) , and differential expression of ck7 and ck20 can facilitate an accurate diagnosis as seen in the present report .
systemic treatment with chemotherapy and/or hormonal therapy is usually employed in patients with confirmed diagnosis of gastrointestinal metastasis ( 1 ) .
the role of surgery is limited to palliation or in patients presenting acutely with obstruction or perforation of the hollow viscus .
the lack of concordance between the clinical , radiological and colonoscopic findings with that of the histological findings resulted in our patient being managed with pre - operative radiotherapy followed with low anterior resection .
the prognosis of gi metastasis from primary breast cancer is poor with few patients surviving beyond two years , although survival up to nine years has been reported .
our patient remains well and disease free four years after treatment for her rectal metastasis .
given the increased survival of breast cancer patients due to the early diagnosis through breast screening and better management with current therapeutic regimens , more unusual presentations of metastatic disease , including involvement of the gastrointestinal tract should be anticipated .
so the recognition of this rare entity ( rectal metastasis from primary breast cancer ) is important , as presentation resembles that of primary rectal carcinoma and differentiation is vital as different therapeutic modalities may be appropriate .

Answer:
gastrointestinal metastasis of the breast cancer is rare and its management varies significantly from that of a primary bowel cancer .
 we report a case of invasive ductal cancer metastasizing to the rectum and masquerading as a rectal primary.a 60 year old caucasian woman presented with fresh rectal bleeding nine years after treatment of her primary breast cancer .
 the investigations revealed features suggestive of primary rectal malignancy and was managed accordingly .
 however , the surgical histopathology revealed poorly differentiated metastatic adenocarcinoma and the immunohistochemical evaluation confirmed origin from a breast primary .
 she had an uneventful post - operative recovery and remains disease free thus far.the continuing advancement in the management of breast cancer patients with resulting increase in the overall survival will lead to such unusual metastatic presentations .
 hence , the awareness , identification and differentiation of such rare metastatic presentation are important in order to manage the patients appropriately in the future .