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:
we applied the blastp program ( 5 ) to identify , for each predicted protein sequence in the h37rv genome ( genbank accession no .
ae000516 ) . following genbank annotations , we compared 3,972 predicted proteins in h37rv with 4,187 predicted proteins in cdc1551 .
we used a strict search criterion ( e = 10 - 50 ) to identify truly orthologous gene pairs .
we aligned ( 6 ) the putative orthologous pairs of amino acid sequences ( n = 3,428 ) , then imposed this alignment on the dna sequences .
visual inspection of amino acid alignments showed that certain alignments , usually near the n - terminus or c - terminus , had regions of very low sequence identity .
examination of the dna sequences of the corresponding genes showed that these regions of low identity were typically caused by a frameshift in one of the two genomes relative to the other .
whether these frameshifts are biologically real or result from sequencing error was uncertain ; therefore , we eliminated 119 such gene pairs from our data set .
for the remaining gene pairs ( n = 3,309 ) , we computed the proportion of synonymous substitutions per synonymous site ( ps ) and the proportion of nonsynonymous substitutions per site ( pn ) by using nei and gojobori s method ( 7 ) . because values of ps and pn were very low in most cases , we did not correct for multiple hits . because ps values appeared to fall into two groups ( see results ) , we used a simple probabilistic model to separate these two sets of gene pairs .
we assumed that the probability of synonymous substitution followed two separate binomial distributions , designated models a and b , with probabilities of  success
( i.e. , of a synonymous difference ) designated pa and pb , respectively . using the bayes equation , for each gene pair with a given ps value ,
we computed the probability that model a applies , given the observed ps : p(a|ps ) = ( psa ) fa /[(psa ) fa + ( psb ) fb ] , where fa is the frequency of cases to which model a applies , fb the frequency of cases to which model b applies , psa is the binomial probability of obtaining the observed ps , given the number of synonymous sites in the gene and a probability of a synonymous difference equal to pa ; and psb is the binomial probability of obtaining the observed ps , given the number of synonymous sites in the gene and a probability of a synonymous difference equal to pb .
of 3,309 pairs of putatively homologous protein - coding genes in the h37rv and cdc1551 genomes of m. tuberculosis , 2,662 ( 80.5% ) showed no synonymous or nonsynonymous nucleotide differences between the two genomes , and 3,010 ( 91.0% ) showed no synonymous differences between the two genomes .
however , in a small number of gene pairs , the proportion of synonymous differences per synonymous site ( ps ) was surprisingly high . in 13 ( 0.4% )
gene pairs , ps was > 0.01 , and in 3 gene pairs ps exceeded 4% .
these extreme ps values seen in a small number of gene pairs are much higher than generally observed between alleles at neutrally evolving loci in eukaryotes ( 8) .
thus , the comparison of protein - coding genes between the two m. tuberculosis genomes suggested the existence of two distinct groups of gene pairs : a large group having few or no synonymous differences and a much smaller group with a substantial degree of synonymous divergence .
we used a simple probabilistic model ( see methods ) to separate these two sets of gene pairs , designated group a and group b , respectively ( figure ) .
the application of this method showed 11 loci with unusually high ps values and probabilities of assignment to group a of < 50% ( figure ) .
a plot of p(a|ps ) , the probability of assignment of a locus to group a given the observed ps value , as a function of ps at 3,309 loci compared between the h37rv and cdc1551 genotypes of mycobacterium tuberculosis .
the plot shows the bimodal nature of the distribution of ps values , with overall higher values of ps at the 11 loci having p(a|ps ) > 50% .
we assumed that group a members are truly orthologous gene pairs that diverged at the time of the common ancestor of the h37rv and cdc1551 genomes .
group a included 3,298 pairs , with mean ps for all genes of 0.000328  0.000022 standard error .
when ps was estimated for the 3,298 genes concatenated together ( a total of 934,413 synonymous sites ) , an estimate of ps = 0.000348  0.00019 was obtained .
the range of ps values in group a was between zero and 0.012 ; a total of 288 loci in group a had ps values other than zero .
these results show a substantial level of nucleotide diversity , approximately half the level of nucleotide diversity in humans ( 9 ) .
rates of nucleotide substitution per unit time are difficult to estimate in bacteria given the lack of calibration from the fossil record ( 10 ) . to obtain an estimate of the rate of synonymous nucleotide substitution ,
we used published data on comparisons of escherichia coli and salmonella typhimurium ( 11,12 ) , which are believed to have diverged approximately 100 million years ago ( 13,14 ) ( table 1 ) .
this procedure yielded estimates for the last common ancestor of h37rv and cdc1551 in the range of 34,00038,000 years ( table 1 ) .
these estimates are approximately twice previous estimates of the age of the common ancestor of worldwide m. tuberculosis ( 2,3 ) . to obtain the observed mean ps value between h37rv and cdc1551 within 15,00020,000 years would require a rate of synonymous substitution approximately twice that observed in enterobacteria . based on synonymous substitutions between escherichia coli and salmonella typhimurium , assumed to have diverged 100 million years ago ( 13,14 ) .
estimates are shown  standard error , based on standard error of mean ps .
group b consisted of 11 gene pairs with mean ps of 0.0286  0.0050 ( table 2 ) . paired sample t - test of the hypothesis that ps = pn , p<0.01 .
the quantities ps and pn are the proportion of nucleotide difference per synonymous site and per nonsynonymous site , respectively . in enterobacteria , a negative correlation exists between observed proportions of synonymous difference and codon bias ( 11 ) . in the case of mycobacterium ,
codon bias results mainly from the very high third position g+c content of most genes ( 15 ) . in our data , however , we observed no correlation between ps and proportion g+c at third codon positions ( r = -0.010 ; not significant ) .
a number of additional possibilities may explain the occurrence of gene pairs with higher than expected ps values : 1 ) balanced polymorphism .
selectively maintained polymorphisms are expected to be much older than neutral polymorphisms and may even predate speciation events ( 16 ) . in the case of haploid organisms such as bacteria
, balancing selection would take the form of frequency - dependent selection rather than overdominant selection .
2 ) differential deletion . in a multi - gene family , if one member of an orthologous pair of genes were deleted in one genotype , the gene pairs would involve paralogous , not orthologous comparisons .
3 ) horizontal gene transfer . a gene obtained by one of the two genotypes from another bacterial species
one indication of a balanced polymorphism is a higher rate of nonsynonymous than synonymous substitution ( 8) . there was no strong evidence of such selection in the present case ; ps was greater than pn at 10 of the 11 loci , and pn exceeded ps only slightly at one locus ( table 2 ) .
in addition , we compared ps and pn in sliding windows of 30 codons along the length of these genes .
no regions were observed in which pn was greater than ps ( data not shown ) .
thus , there was no evidence of positive selection acting on specific regions of these genes .
on the other hand , differential deletion can probably explain some cases , most notably members of the pe multi - gene family ( 11 ) ( table 2 ) .
the remaining gene pairs are possibly cases of horizontal gene transfer ( table 2 ) , for which there is some recent evidence in m. tuberculosis ( 17 ) .
our results did not support the hypothesis that the common ancestor of m. tuberculosis was relatively recent ( 2 ) .
rather , the pattern of nucleotide substitution at synonymous sites suggested a divergence time for the two available genotypes of this species approximately 35,000 years ago .
since h37rv and cdc1551 represent two genotypes sampled from within the species , they are probably not the most divergent genotypes possible .
thus , the last common ancestor of m. tuberculosis likely occurred considerably earlier than 35,000 years ago .
while the difference between an estimate of 15,00020,000 years and one of 35,000 years is not large on an evolutionary time scale , such a difference is substantial on the scale of human history .
for example , the existence of two genotypes in the current population of m. tuberculosis with a common ancestor at 35,000 years is evidence against the hypothesis that m. tuberculosis arose , presumably from m. bovis , at the time of human domestication of cattle ( 18 ) .
our result is thus consistent with phylogenetic analyses based on insertion - deletion events , which suggest that the m. tuberculosis lineage was a human pathogen well before the origin of m. bovis ( 19 ) .
thus , along with recent evidence of an ancient origin and extensive polymorphism in the malaria parasite plasmodium falciparum ( 20,21 ) , our study provides evidence against the long - held view that virulent pathogens are invariably evolutionarily recent ( 22 ) .
our estimate is conservative because the rate of synonymous substitution may actually be lower in mycobacterium than in enterobacteriaceae , given the highly skewed g+c content in the former .
furthermore , our estimate of the mean proportion of synonymous difference was conservative because we excluded 119 loci with potential frameshifts between the two genotypes as well as a set of 12 loci with unusually high ps values .
in addition to the 12 loci assigned to our group b , certain other loci might also have originated from horizontal gene transfer . however , even if horizontal gene transfer has occurred at other loci besides those in group b , eliminating further loci with relatively high ps values from group a will not affect the results greatly .
for example , if we eliminate the 10 loci with highest ps values from group a , mean ps will be reduced only to 0.000299 , and the estimated age of the common ancestor will be barely affected .
the degree of polymorphism observed in this study is unlikely to have been substantially influenced by sequencing errors .
the error rate for finished sequences from the institute for genomic research ( where cdc1551 was sequenced ) has been independently estimated at < 1 in 88,000 bases ( 23 ) . assuming a similar error rate for both 4.4 mega - bp m. tuberculosis genomes
, we would expect to see approximately 100 differences between them due to sequencing errors .
approximately 21 such differences would be expected in the 938,778 synonymous sites in group a and group b genes .
in fact , 411 synonymous differences were observed at these sites ; thus , even if present , sequencing errors are likely to have made up only a small fraction ( approximately 5% ) of the total synonymous polymorphism . at such a rate ,
sequencing errors would have little effect on our estimates of nucleotide diversity at synonymous sites or the age of the common ancestor of the two genomes .
in addition , the hypothesis that the single nucleotide polymorphisms ( snps ) observed between these genotypes are real received strong support from a recent study that observed a number of the same snps in clinical isolates ( 24 ) . moreover , since sequencing errors are expected to occur at random with respect to the reading frame of coding sequences , the fact that mean ps exceeded mean pn in both group a and group b was strong evidence against the hypothesis that a substantial proportion of the observed polymorphism was due to sequencing error .
simple considerations of probability can explain why earlier studies produced relatively low estimates of this species age .
if we assume that the per - site probability of a synonymous difference between two m. tuberculosis genomes is equal to the mean ps observed between h37rv and cdc1551 ( 0.000328 ) , then the probability is approximately 95% that no synonymous differences will be seen in a gene with 150 synonymous sites .
the probability that no synonymous differences will be seen in 10 such loci chosen at random is approximately 60% , and the probability that no synonymous differences will be observed at 20 such loci is approximately 37% . on the other hand , the probability that no synonymous differences will be seen at 100
these calculations emphasize the need to examine a very large number of nucleotide sites to obtain a reliable estimate of nucleotide diversity and thus of the age of the most recent common ancestor in cases where the frequency of substitution is less than one in a thousand .
even when the frequency of substitution is between one in a thousand and one in a hundred , substantial stochastic error is possible if the number of loci examined is small .
thus , any study that estimates population parameters from nucleotide sequence data needs to survey a substantial number of loci .
these considerations are particularly important in the case of pathogenic microorganisms , where a number of factors ( including both natural selection and horizontal gene transfer ) may lead to substantial differences among loci with respect to the level of nucleotide diversity .
comparison of two complete genomes of m. tuberculosis showed a greater extent of sequence polymorphism than would be expected on the basis of previous studies , in turn suggesting that analysis of additional genomes will likely show further polymorphism .
polymorphism in any species of pathogen may complicate therapeutic strategies because it implies the existence of variation on which selection can act , including selection imposed by human vaccines and pharmacologic agents ( 20 ) .
on the other hand , known polymorphisms may prove useful to investigators in reconstructing the evolutionary relationships among clinical isolates and in providing markers for understanding the genetic basis of complex phenotypic traits .

Answer:
comparison of the pattern of synonymous nucleotide substitution between two complete genomes of mycobacterium tuberculosis at 3,298 putatively orthologous loci showed a mean percent difference per synonymous site of 0.000328  0.000022 .
 although 80.5% of loci showed no synonymous or nonsynonymous nucleotide differences , the level of polymorphism observed at other loci was greater than suggested by previous studies of a small number of loci .
 this level of nucleotide difference leads to the conservative estimate that the common ancestor of these two genotypes occurred approximately 35,000 ago , which is twice as high as some recent estimates of the time of origin of this species .
 our results suggest that a large number of loci should be examined for an accurate assessment of the level of nucleotide diversity in natural populations of pathogenic microorganisms .


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:
in dentistry , the concept of aesthetics is extremely subjective and is related to beauty , harmony and the needs of the patient .
the interactions between new restorative materials and techniques allow the reproduction of dental structures , restoring form and function in such a way that restorative procedures become imperceptible .
nevertheless , during the evaluation of aesthetically compromised teeth , we encounter unfavorable clinical situations of great complexity , characterized by deep invasions of the mineralized structures .
the reproduction of the optical characteristics of the teeth , such as translucency , opalescence and fluorescence , requires a considerable knowledge of restorative techniques and the materials currently available .
dental enamel defects have been associated with a broad spectrum of aetiologies , including genetic and epigenetic factors such as systemic , local and environmental factors .
a serious disturbance that occurs during the stages of enamel formation will impact the quality and/or quantity of the enamel formed , depending on the phase of amelogenesis that is affected and the duration of the stimulus on the ameloblasts .
the consequence of this disturbance in the formation of the organic enamel matrix is enamel hypoplasia , which can be characterized as small grooves , depressions and cracks in the enamel surface that can be viewed in mild cases .
this article presents a case report of a restorative treatment of enamel hypoplasia using hybrid composite resin to mask color alteration and enamel defects of the anterior upper teeth .
a 22-year - old female patient was referred to the dental clinic , reporting a visual discomfort from the presence of irregularities and discoloration in the maxillary incisors . dental history and
clinical examination revealed that she had a soft form of enamel hypoplasia [ figure 1 ] .
clinical examination also evidenced an enamel defect in the maxillary lateral and central incisors , with rough surfaces with irregular limits that principally involve the middle third of the crown [ figure 2 ] .
initial clinical aspect of the maxillary incisors a buccal view of the central and lateral incisors with hypoplastic alterations the clinical situation revealed that it was not possible to re - establish aesthetics and function without the use of a restorative procedure .
the position and pattern of the enamel irregularities , the occlusion and a tooth remnant with a large substrate suggested that a composite resin restoration would be a reliable option for this case .
the patient was systemically healthy , presented an overall plaque index and gingival index of below 10% and the restorative area was free from visible plaque .
a slight enameloplasty , using a spherical 1015f diamond bur ( kg sorensen , so paulo , brazil ) and manual instruments , was performed on both the irregularities and the limits of the tooth defect [ figures 3 and 4 ] .
the regularization of the defects created a good substrate that was favorable for adhesive restorations .
delimitation of the tooth irregularities with graphite enameloplasty with a spherical diamond bur for smoothing out defects the color was recorded using the vitapan classical scale ( vita zahnfabrik , bad sckingen , germany ) , and the shade a2/a3 was considered as the initial color .
briefly , the dental surface was acid etched ( 35% phosphoric acid ) [ figure 5 ] , rinsed for 30 s and dried with absorbent paper .
a two - component adhesive system ( adhese , ivoclar vivadent ag , schaan , liechtenstein ) was applied on the dentin and the enamel and was light - cured for 10 s with an intensity of 1400 mw / cm ( radii led curing light , sdi , australia ) [ figure 6 ] .
the dental surface was acid etched ( 35% phosphoric acid ) a two - component adhesive system was applied on the dentin and on the enamel a combination of the incremental and stratified layering technique was used to fill the tooth using a highly aesthetic nanohybrid composite resin , ips - empress ( ivoclar vivadent ag ) .
the composite was added in increments of 1.52 mm and was light - cured after every layer , according to the manufacturer 's instructions .
first , the dentin was simulated with a thin layer of a microhybrid composite ( da3 ) and a final layer with an enamel composite ( ea2 ) , which was placed with a fine # 2 brush ( cosmedent , chicago , usa ) for fine detailing / texturizing to simulate the enamel , increasing the final brightness of the restoration [ figure 7 ] . a clinical view of the central incisor immediately after the restorative procedures
the contouring was refined using 30-blade carbide trimming burs ( 9714ff , kg sorensen ) , and the final polishing was performed with a high - luster polishing paste ( opal l , renfert gmbh , hilzingen , germany ) using goat - hair brushes and cotton buffs ( renfert gmbh ) .
four months after the restoration , a good final aspect was observed and the lateral smile view exhibited an imperceptible restoration [ figures 8 and 9 ] .
with the valuation of aesthetics , minimally invasive restorative techniques have provided an expansion of the current conservative philosophy .
nevertheless , during the evaluation of aesthetically compromised teeth , we encounter adverse clinical conditions of great complexity , marked by the invasion of the mineralized structures at depth .
enamel hypoplasia is an incomplete or defective formation in the organic matrix of the enamel and remaining certain areas susceptible to decay ; it is responsible for a major proportion of lesions .
the irregularities present in a hypoplasia provide favorable conditions for the retention of plaque and the early development of caries lesions , which progress and reach deep into the enamel and the dentin .
one of the signs of hypoplastic lesions is diminishing enamel luster and dental surfaces that have become eroded with cavitations and irregular wear because of the loss of the microanatomy affecting the color , morphology and texture of teeth . on some occasions , hypoplasia is mistaken for fluorosis ; however , enamel hypoplasia is an incomplete or defective formation in the organic matrix of the enamel , triggered by diseases , systemic disorders , trauma and infections in the pulp of deciduous teeth .
it manifests with partial or complete absence of the enamel , which can be systemic ( when it affects a group of teeth ) or local ( when it has asymmetric distribution and is relegated to a single tooth ) . because it is neither fully transparent nor fully opaque ,
some modern composites provide optical similarities consistent with natural teeth , yielding satisfactory levels of opalescence , value and chroma .
it is important to consider that the final restoration is dependent on both the thickness and the varying degrees of translucency and opacity of the several layers of the composite . of all dental structures
describe a minimally invasive technique performed in cases of enamel hypoplasia based on enamel microabrasion and complemented with composite resin restorations .
the procedures employed are simple , but they require knowledge of the real causes of the staining and comprehension of restorative techniques . various treatment protocols may be performed , depending on the level of involvement and the severity of the lesions .
composite resin restorations are fully capable of reproducing the appearance of a natural tooth with highly aesthetic outcomes . in this context
, the main goal of the treatment of enamel hypoplasia is to re - establish the anatomical harmony between occlusion , function and aesthetics and to restore patient self - esteem , promoting social and psychological benefits .
in conclusion , this case report demonstrates that restorative rehabilitation , in addition to promoting health , may provide a more favorable aesthetic appearance for the smile , matching the tooth polychromatic and raising the self - esteem of the patient .

Answer:
enamel hypoplasia is a developmental defect of the enamel that is produced by a disturbance in the formation of the organic enamel matrix , clinically visible as enamel defects .
 disorders that occur during the stages of enamel development and maturation reduce the amount or thickness of the enamel , resulting in white spots , tiny grooves , depressions and fissures in the enamel surface .
 the complexity and intensity of the dental deformity lesions will conduct the ideal treatment - associating conservative techniques .
 this article presents a case report of a restorative treatment of enamel hypoplasia using hybrid composite resin to mask color alteration and enamel defects .
 an aesthetic appearance that respects the tooth polychromatic and the self - esteem of the patient can be achieved with this approach .


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:
adenomatoid odontogenic tumor ( aot ) is a benign , slow - growing , and noninvasive odontogenic lesion associated with an impacted tooth .
the presence of so - called unique  duct - like structures  under microscope imparts the tumor a glandular , i.e. , adenomatoid appearance .
the tumor is also known as  two third 's tumor  because about 2/3 cases occur in maxilla , about 2/3 cases are diagnosed in young females during the second decade , 2/3 cases are associated with an impacted tooth and in 2/3 cases , impacted tooth is canine .
we present a case of unusually large aggressive aot in the maxilla associated with impacted third molar .
a 19-year - old male reported with a chief complaint of painless mass over the left side of face and upper left back tooth region since 6 months .
initially , pea - sized and asymptomatic swelling appeared in upper left back tooth region .
three months later , swelling also appeared below left eye , initially pea - sized .
he gave h / o exfoliation of multiple teeth from the same region within these 6 months . on examination , solitary , smooth , roughly spherical - shaped swelling was present on the left side of face below eye .
swelling extends from infraorbital region until malar prominence and from medial to lateral corner of left eye measuring approximately 5.0 cm  5.0 cm in maximum dimensions .
there was marked obliteration of palpebral fissure of the left eye [ figure 1a ] .
intraorally , there was a solitary roughly oval - shaped growth in the left maxillary region , obliterating the buccal vestibule .
growth was extending from canine region till retromolar area along alveolar ridge measuring approximately 7 cm  4 cm .
overlying mucosa was erythematous , edematous , and inflamed . both extraorally and intraorally , swelling was firm , noncompressible , nonfluctuant , nontender , nonreducible , and nonpulsatile .
( b ) intraoral photograph showing lesion involving palate , alveolar ridge , and buccal vestibule orthopantomogram revealed a huge , diffuse radiolucent lesion extending throughout left maxilla from canine till retromolar region . the lesion was associated with an impacted permanent upper left third molar , which was found to be present below floor of the orbit .
computed tomography scan [ figure 3a  c ] demonstrated a large cystic expansile radiolucent lesion with flecks of calcification of varying sizes .
the buccal and palatal bony expansion was remarkable , and resorption of bone with perforation was evident .
maxillary sinus was completely opaque . on the basis of these radiological findings , aot and pindborg tumor
orthopantomogram showing a large radiolucent lesion involving left maxilla , and impacted upper left third molar teeth displaced below floor of orbit by the lesion ( red circle ) ( a - c ) computed tomography scan revealing the expansile radiolucent lesion with few radio - opaque flakes .
there is remarkable bony expansion and thinning and discontinuity of the palatal and buccal cortices .
having accessed the tumor extraorally as well as intraorally , subtotal maxillectomy was performed , and the involved teeth were also removed [ figure 4b ] .
the surgical defect was simultaneously reconstructed using temporalis myofascial flap [ figure 4d ] healing was uneventful .
six months after surgery , computed tomogram was done which revealed complete eradication of the lesion [ figure 5a  c ] .
there was no evidence of any recurrence 1 year after the surgery [ figure 6a and b ] .
( a - d ) operative photographs ( a - c ) six months postoperative computed tomogram shows normal healing and no signs of recurrence ( a ) one year follow - up photograph .
( b ) one year follow - up intraoral photograph with normal healing histological examination revealed a partially cyst - like cavity lined with the fibrous capsule . rounded and rosette - like aggregates of odontogenic epithelial cells with sparse areas of eosinophilic material could be visualized .
the characteristic rounded and rosette form lined with a single layer of polarised cuboidal or columnar epithelium cells giving it the adenomatoid appearance ( h and e , 400 )
aot has three clincopathological variants , namely intraosseous follicular ( 73% ) , intraosseous extrafollicular ( 24% ) , and peripheral ( 3% ) .
the intraosseous follicular type is associated with an impacted tooth as in our case , whereas the intraosseous extrafollicular type has no association with an impacted tooth and the peripheral variant is soft tissue component , attached to the gingival structures .
the lesion often leads to the expansion of the involved bone and the displacement of the adjacent teeth . owing to the slow growing and painless nature of the tumor , the patients tolerate the swelling for a long duration , sometimes years until it produces an obvious esthetic deformity .
it may rarely show aggressive nature such as gaining unusually large size or extending into the intracranial space .
radiographically , the lesion often demonstrates as a unilocular radiolucency associated with an impacted tooth . in certain cases , small radiopaque spots ( calcifications )
differential diagnosis of aot includes dentigerous cyst , calcifying odontogenic cyst ( coc ) , calcifying odontogenic tumor ( cot ) ( pindborg tumor ) , and odontogenic keratocyst .
radiolucency with multiple radiopaque foci ( particularly when the radiolucency surrounds a portion of the root or entire tooth ) is suggestive of an aot rather than a coc / cot .
histologically , aot is mostly surrounded by a well - developed fibrous connective tissue capsule .
the tumor is usually composed of spindle - shaped or polygonal cells forming sheets , rosettes or whorled masses in a sparse connective tissue stroma .
the amorphous eosinophilic material is present between the epithelial cells as well as in the center of these rosette - like structures .
the large size of this lesion has been attributed to a higher growth rate in younger patients and a delay in seeking treatment .
however , in our case , the lesion was extremely large in size and expansile .
therefore , subtotal maxillectomy with simultaneous reconstruction of surgical defect with temporalis myofascial flap was planned and carried out .
the case presented is rare in occurrence because of certain atypical features such as unusual large size , aggressive behavior , the involvement of maxillary third molar , third molar present below floor of orbit , significant bony expansion , and cortical perforation . under general anesthesia ,
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .
the authors certify that they have obtained all appropriate patient consent forms . in the form the patient(s )
has / have given his / her / their consent for his / her / their images and other clinical information to be reported in the journal .
the patients understand that their names and initials will not be published and due efforts will be made to conceal their identity , but anonymity can not be guaranteed .

Answer:
adenomatoid odontogenic tumor ( aot ) is a rare tumor comprising only 3% of all odontogenic tumors .
 it is a benign , encapsulated , noninvasive , nonaggressive , slowly growing odontogenic lesion associated with an impacted tooth .
 these lesions may go unnoticed for years .
 the usual treatment is enucleation and curettage , and the lesion does not recur . here
 , we present a rare case of an unusually large aggressive aot of maxilla associated with impacted third molar . the authors also discuss clinical , radiographic , histopathologic , and therapeutic features of the case .
 subtotal maxillectomy with simultaneous reconstruction of the surgical defect with temporalis myofascial flap was planned and carried out .


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Sulfamate Esters Guide Selective Radical-Mediated Chlorination of Aliphatic C\xe2\x80\x93H Bonds

Paper sections:

Late-stage alkyl C–H functionalization[1] facilitates investigations into pharmaceutical small molecule leads.[2] Unfortunately, position-selective reactivity is difficult to achieve at unactivated C(sp3)–H centers, which have high bond dissociation energies (90–105 kcal/mol), are not acidic (pKa ≥ 50), and do not integrate more polarizable and electronically accessible π-orbitals. Consequently, in most efficient atom-transfer processes, site-selective activation originates at an electron-rich, sterically accessible bond (Scheme 1A),[1b,d,3] or is controlled kinetically by a directing group (Scheme 1B). A hydroxyl group is attractive as a directing moiety because alcohols are common within readily available small molecules. To our knowledge, there are no general strategies for aliphatic γ-C–H functionalization guided by a masked alcohol.[4,5] Herein described are the first experiments to demonstrate that sulfamate esters[6,7] can mediate 1,6-hydrogen-atom transfer (HAT) processes to guide the light-promoted chlorination of unactivatedγ-C(sp3)–H centers.

Our strategy for γ-functionalization is inspired by the modern resurgence of interest[8,9] in the Hofmann-Löffler-Freytag (HLF)[10–12] reaction. In traditional HLF processes, position selectivity arises based on formation of an intermediate nitrogen-centered radical that engages in a 1,5-HAT process[13] through a kinetically favored, six-membered transition state.[14] By contrast, we anticipate sulfamate esters may be capable of mediating 1,6-HAT processes, which are rare[15] as they are expected to proceed through seven-membered transition states, which are often kinetically disfavored.[16] We hypothesize that sulfamate esters enable 1,6-HAT because their elongated O–S and S–N bonds (∼1.58 Å) and compressed O–S–N bond angles (∼103°)[17] geometrically favor a seven-membered ring transition state for C–H abstraction. The site-selectivity available through these reactions complements that achieved using traditional HLF chlorination transformations,[18] alternative guided chlorination methods,[19] or site-selective intermolecular[20] chlorination processes.

This approach is demonstrated in the course of site-selective chlorine-transfer to convert N-chlorinated sulfamate esters 1 to alkyl chlorides 2 (Scheme 1B). Predictable control has proven more challenging in C(sp3)–H chlorination[21] than bromination reactions,[12d,22,23] owing to the promiscuity of chlorine radical promoted hydrogen-atom abstraction. Nevertheless, alkyl chlorides are useful synthetic intermediates, and components of bioactive small molecules, with >2000 known chlorine-containing natural products.[24] Consequently, new technologies for selective aliphatic C–H chlorination have potential to streamline syntheses of bioactive small molecules.[25]

To minimize mechanistic uncertainty, we chose to generate nitrogen-centered radicals by using light to homolyze nitrogen–chlorine bonds of N-chlorosulfamate esters 1. N-chlorosulfamate esters 1 are readily available from sulfamate esters 3[26] upon treatment with trichloroisocyanuric acid or tert-butyl hypochlorite (see supporting information for details).As anticipated, photolysis of pentyl methylchlorosulfamate ester 1a results in selective γ-chlorination at a methylene center (Table 1, entry 1, C–H bond dissociation energy (BDE) ∼ 98 kcal mol–1).[27] This reaction does not occur in the absence of light, indicating that photolysis initiates the reaction.

Chlorine-transfer proceeds from N-methyl-, N-tert-butyl-, N-trifluoroethyl- and N-2-(pyridin-2-yl)isopropylchlorosulfamate esters 1a–d (Table 1, entries 1–7). The corresponding series of sulfamate esters 3 are predicted to differ in terms of N–H bond acidity[28] by more than three pKa units, indicating that the reaction tolerates broad electronic variations across N-alkyl substituents. In all of these cases, the remaining mass balance can be accounted for principally by reduced 3. Notably, in the reaction of substrate 1b, <2% yield of δ-chlorinated product 4b (not depicted) can be detected in the crude reaction mixture along with desired γ-chlorinated 2b.While N-alkylsulfamate esters facilitate chlorination, some N-arylsulfamate esters may not engage in productive guided chlorine-transfer processes, as photochemical irradiation of arylated 1e generates a complex mixture of products.

In these chlorine-transfer processes, site-selectivity is orthogonal to that available through most atom-transfer processes reliant on innate selectivity. In the productive transformations of N-chlorinated 1a–d, chlorinated alkanes 2a–d are formed with exquisite γ-selectivity, despite the fact that δ-functionalization is expected to be favored under conditions that rely on inherent selectivity (Table 1; Scheme 1A).

Guided selectivity is preserved across a range of O-alkyl sulfamate esters (Table 2). For menthol-derived 1f, C(5)–H and C(8)–H bonds are expected to have very similar electron densities.[29] Nevertheless, unguided tertiary-selective intermolecular oxidation[29] and amination[30] processes result in selective functionalization of analogues at C(5), presumably because the C(8)–H bond is sterically encumbered.[29] By contrast, under the described conditions, chlorination occurs exclusively at C(8)–H, which is poised to interact with the sulfamate ester nitrogen-centered radical (entry 1) via a seven-membered transition state. This position-selectivity is analogous to that displayed in iron- and manganese-nitrene-mediated intramolecular amination reactions of sulfamate esters.[31,32]

Furthermore, the directed chlorination reaction overcomes the innate site-selectivity that arises from inductive deactivation in unguided oxidation processes. In unguided C–H functionalization reactions, proximity to inductively electron-withdrawing groups deactivates C–H bonds to oxidation. This phenomenon is evident when 3,7-dimethyloctanol is masked with an electron withdrawing group, and engages in undirected fluorination,[33] oxygenation,[34] amination,[35] azidation,[36] or trifluoromethylthiolation[37] processes that functionalize C(7) in preference to C(3). By contrast, the sulfamate ester-guided chlorination installs chlorine at the electronically deactivated C(3) position (entries 2–3).

Moreover, this guided functionalization process overcomes selectivity that typically arises from differences in bond strength. Pendant silyl ether 1i undergoes efficient and selective γ-chlorination, without oxidation of the weak etherial C–H bonds (BDE ∼ 85 kcal mol−1, entry 4).[27]

In addition to differentially masked diols, the reaction conditions are compatible with a variety of functional groups. Sulfamate esters derived from N-protected amino alcohols engage in selective atom-transfer, as phthalimidyl 1j provides chlorinated 2j in 82% isolated yield (entry 5). As noted previously, the reaction also allows pendant heteroaromatic moieties (Table 1, entry 7) and fluorides (Table 1, entries 4–6; Table 2, entries 1, 3–5, 9).

This method transforms C(sp3)–H bonds at secondary, tertiary (BDE ∼ 96 kcal mol–1),[27] and benzyliccenters (BDE ∼ 90 kcal mol–1)[27] in synthetically useful yields (entries 1–8). Generally, chlorination of γ-C(sp3)–H centers occurs in preference to β-C–H centers, even when the γ-C–H bond is primary and significantly stronger (BDE ∼ 101 kcal mol−1)[27] than a secondary β-C–H bond. For example, chlorination of propyl tert-butylsulfamate ester 1m and (–)-borneol derivative 1n occur at the stronger primary C–H bonds, albeit with diminished efficiency (entries 8–9). While each of these substrates displays a geometrically accessible β-methylene center, chlorination at these positions is not detected. Instead, dehalogenated sulfamate esters 3m and 3n are the primary by products of these transformations. An analogous reactivity trend has been documented with White's manganese-catalyzed intramolecularamination with sulfamate esters.[32]

In principle, this chlorination reaction could proceed through a closed cycle and/or a radical chain propagation mechanism (Scheme 2). In either pathway, initiation would occur by light-promoted N–Cl bond homolysis, thereby converting N-chlorosulfamate ester 1b to chlorine radical and sulfamyl radical 5b. The resulting nitrogen-centered radical 5b mediates an intramolecular 1,6-HAT to generate a carbon-centered radical 6b with exquisite position selectivity. Subsequent divergence in carbon–chlorine bond forming events then distinguishes between the proposed pathways. In the closed radical cycle mechanism, intermediate carbon-centered radical 6b recombines with the chlorine radical to terminate the reaction and provide 2b (not depicted). Alternatively, carbon-centered radical 6b could engage in chlorine-atom abstraction with another equivalent of N-chlorosulfamate ester 1b (Scheme 2). This sequence would release desired halogenated 2b, along with another equivalent of radicalloid 5b, which could propagate this chain reaction.

These mechanistic hypotheses differ in terms of the number of product equivalents that can be generated per absorbed photon, a relationship that defines quantum yield (Φ). While a closed radical cycle could furnish a maximum of one product molecule per absorbed photon (Φ ≤ 1), a radical chain propagation mechanism could provide multiple equivalents of the product per absorbed photon (Φ > 1).

Quantum yield measurements have been performed to provide insight into the operative reaction mechanism,[38] and provide evidence that the reaction proceeds through a light-initiated chain propagation mechanism. Briefly, standard chemical actinometry using potassium ferrioxalate allowed us to determine the photon flux of a fluorimeter at 313 nm.[38,39] After 15 minutes of irradiation of N-chlorinated 1b in benzene at 313 nm in the calibrated fluorimeter, 68% conversion to chloroalkane 2b is observed. This yield corresponds to 77 equivalents of product formed per absorbed photon (Φ = 77), indicating that this reaction proceeds through a chain propagation mechanism.

This sulfamate ester-guided HLF reaction is expected to provide a powerful and general platform to complement current HLF technologies. This research is among the first to establish that sulfamate esters can mediate 1,6-HAT such that the generated carbon-centered radicals can be trapped efficiently in guided intermolecular reactions. Furthermore, the method provides efficient access to secondary and tertiary alkyl chlorides, a valuable class of synthetic intermediates, with novel and predictable site-selectivity.

Answer: Masked alcohols are particularly appealing as directing groups because of the ubiquity of hydroxyl groups in organic small molecules. Herein, we disclose a general strategy for aliphatic \xce\xb3-C(sp3)\xe2\x80\x93H functionalization guided by a masked alcohol. Specifically, we determine that sulfamate ester-derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide \xce\xb3-C(sp3)\xe2\x80\x93H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.


Question:
You will be shown the title of a chemistry paper, together with sections excerpted from the body of the paper. The paper sections may include HTML tags like `<p>` and `</p>`; please ignore these. Your task is to write an abstract for the paper. Your response should include the abstract and no other text.

Title:
Two-photon uncaging of \xce\xb3-aminobutyric acid in intact brain tissue

Paper sections:

Two-photon (2P) excitation is a method that has revolutionized many areas of biological science as it enables three-dimensionally defined excitation of chromophores in biological tissue1,2. We previously developed 4-methoxy-7-nitroindolinyl-L-glutamate (MNI-Glu3
1) and 4-carboxymethoxy-5,7-dinitroindolinyl-L-glutamate (CDNI-Glu4
2) for 2P uncaging in mammalian brain slices. Depending on the size of the 2P excitation volume, we mimicked synaptic quantal release of glutamate using diffraction limited 2P uncaging3 or fired action potentials and mapped unitary synaptic connections in a large volume of the neocortex using macro 2P uncaging5. Although a variety of caged glutamate probes have been reported6, γ-aminobutyric acid (GABA), has received comparatively little attention from chemical biologists, and 2P uncaging of this vital neurotransmitter has not been reported. We have synthesized a new caged GABA derivative (CDNI-GABA, 3) that undergoes 2P photolysis in living brain slices with low power (ca. 10 mW at 720 nm) and at low concentrations (0.40-1.35 mM). Two-photon uncaging of CDNI-GABA over the axon initial segment (AIS) of CA1 pyramidal neurons enabled high resolution functional mapping that showed a punctate distribution of GABA-A receptors. Successive functional mapping of the apical dendrite with CDNI-GABA and MNI-Glu revealed no correlation between the distribution of GABA and glutamate receptors. CDNI-GABA uncages rapidly and efficiently (quantum yield of 0.60), therefore this new caged GABA probe is a useful addition to the optical toolbox available to neuroscientists.

The synthesis of CDNI-GABA (Fig. 1a) is outlined in Supplementary Fig 1. The quantum yield for uncaging of CDNI-GABA was determined by comparison with a known photochemical standard. HPLC analysis of the time-course of photolysis showed that CDNI-GABA was photolyzed about seven times faster than MNI-Glu, implying that the quantum yield of photolysis was 0.60 (± 0.02, n=3). The presence of a strongly electron withdrawing group at the 5-position promotes deprotonation of the C-2 hydrogen, enhancing the quantum yield of bond scission to give the desired uncaged amino acid.

Photolysis of CDNI-GABA near the edge of the perisomatic apical dendrite of CA1 pyramidal neurons (Fig. 1b) with 6.3 mW for 1 ms evoked fast inhibitory postsynaptic potential currents (which we call "2pIPSCs", see Fig. 1c) that were blocked by picrotoxin (PTX 4, Fig. 1d). Because power requirements for 2P uncaging of CDNI-GABA were low, we reasoned that this new caged GABA could enable three-dimensional mapping of receptor densities3, without fear of photodamage. Functional mapping at four z-sections (Fig. 1e) revealed that the axial resolution of the evoked current was close to the diffraction limit (Fig. 1f; full-width at half-maximum (FWHM) = 2.1 μm, microscope resolution 1.4 μm at 720 nm). These data show that non-linear excitation particularly helps limit axial uncaging in comparison to UV-visible (i.e. 1P) excitation. Similar benefits have been reported for 2P uncaging of glutamate in brain slices7-10.

We established that the evoked currents arose from 2P excitation1 by mapping the GABA-A receptor density across the surface of the apical dendrite with and without laser mode-lock (Fig. 1g-i). No current was evoked with a mode-unlocked laser (Fig. 1h), whereas similar functional receptor maps were detected before and after this experiment with a mode-locked laser (Fig. 1g,i).

Two-photon uncaging of CDNI-GABA allowed us to approximate miniature IPSCs (mIPSCs), as the rise time and decay kinetics of 2pIPSCs were similar to those of spontaneous mIPSCs (Fig. 1j, and Supplementary Table). Specifically, the average rise time (20-80%) of the 2pIPSCs was 2.0 ± 0.2 ms (6-112 events per cell, n = 6 cells), whereas the average rise time of the spontaneous mIPSCs was 1.5 ± 0.2 ms (10-66 events per cell, n = 6 cells). The average rise times of the 2pIPSCs and mIPSCs were not significantly different (P = 0.075, paired t test). The decay half-times were 24.7 ± 2.5 ms (2pIPSCs) and 10.5 ± 1.1 ms (mIPSCs), which were significantly different (P < 0.005, paired t test, n = 6 cells). Since 2P uncaging of CDNI-GABA on the perisomatic dendritic membrane showed a dense distribution of GABA-A receptors (Fig. 1e), the longer decay time of the 2pIPSC probably reflects the increased clearance time of uncaged GABA from clusters of GABA-A receptors near the focal volume of 2P excitation.

Funtional mapping with CDNI-GABA was reproducible (Fig. 1g,i correlation coefficient (CC) of 0.65 ± 0.02, n = 4 pairs of maps in 4 cells), implying that hot spots of GABA responses do not rapidly diffuse laterally. If such hot spots were GABAergic synapses, they should be devoid of glutamate receptors, because GABAergic and glutamatergic synapses are structurally different11. Comparison of functional maps of GABA-A and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors on the same proximal dendrites (Fig. 2a,b) showed CC of 0.22. These data suggest that the hot spots of functional GABA-A receptors were anchored clusters of GABA-A receptors, probably GABAergic postsynaptic sites, and that the number of functional GABA-A receptors varied among synapses.

One of the major functions of GABA-A receptors is to modulate the generation of action potential in the AIS where sodium channels are densely distributed12. Although immunological staining has revealed that axo-axonic cells innervate the AIS via GABAergic synapses with GABA receptors13,14, the functional distribution of GABA-A receptors along the AIS has not been clarified. Thus, we performed three dimensional mapping of GABA-A receptors on the AIS. We detected heterogeneous responses of functional GABA-A receptors along the AIS over 40 μm (Fig. 2c,d). The kinetics of the currents (Fig. 2e) was similar to that obtained at the somatic membrane. The detection of functional GABA-A receptors on the AIS needed a higher energy of 2P excitation than that used at the perisomatic apical dendrite. Immunoelectron microscopy has shown that synaptic size and the number of synaptic GABA-A receptors in the AIS are smaller than those in the soma14. Our data confirm this, showing a functionally disparate distribution of inhibitory receptors at the major input and output pathways of pyramidal neurons.

The most widely used15 caged GABA (α-carboxy-o-nitrobenyl[CNB]-GABA16
5) has been reported to be a mild antagonist of GABA-A receptors17. Consequently we tested the basic pharmacology of CDNI-GABA, the structurally related CNI-GABA 6 and the widely used MNI-Glu. Concentrations of 0.325 mM CNI-GABA when bath-applied in the artificial cerebrospinal fluid (aCSF) perfusate have no effect on the tonic firing of neurons of the deep cerebellar nuclei in brain slices18. We found that a much higher concentration of CNI-GABA (10 mM), which we used for 2P uncaging (data not shown), or CDNI-GABA (10 mM) inhibited GABA-A receptors currents in acute hippocampal slices when co-applied with GABA itself (Supplementary Fig. 2a and 2b). Much to our surprise the same concentration of MNI-Glu (as used in Fig. 2) had similar effects (Supplementary Fig. 2b). These findings implied that high concentrations of structurally diverse caged transmitters such as MNI-Glu, CNI-GABA, and CDNI-GABA block GABA-A receptors. In particular, the block of GABA-A receptors by MNI-Glu indicates a potential risk for caged neurotransmitters to affect receptors other than their intended target. The lower concentration of CDNI-GABA (1.35 mM) used for Fig. 1 and Fig. 2 still reduced GABA-A receptors current when co-applied with 0.1 mM GABA by 70 % (Supplementary Fig. 2a and 2b). Spontaneous mIPSCs were surpressed during puff application of 1.35 mM CDNI-GABA (Supplementary Fig. 2c.) However, 0.4 mM CDNI-GABA reduced currents by only 22 % (Supplementary Fig. 2b). Further, the antagonism on the size and frequency of spontaneous mIPSCs at 0.4 mM was mild, as almost immediately after the end of the puff the standard-sized signals of spontaneous mIPSCs reappeared (Supplementary Fig. 2d). We tested 2P uncaging at this concentration and found it was feasible (Supplementary Fig. 3). Thus CDNI-GABA can be used for 2P functional mapping under conditions of very mild antagonism towards GABA-A receptors.

A variety of caged GABA compounds have been reported over the past 14 years16,18-21. However, only CNB-GABA16 has been used by many laboratories15, and so the properties of this important compound are compared with CDNI-GABA, along with recent alternative approaches18-20, in Table 1. CDNI-GABA is not only uniquely effective for 2P functional mapping (Figs. 1,2), it is significantly more photochemically efficient for UV-visible photolysis (i.e. ε.φ ) than the other caged GABAs (Table 1).

The inherent non-linear nature of 2P microscopy means that axial excitation is greatly restricted when compared with UV-visible excitation1,2. This property has enabled several laboratories to achieve stimulation of AMPA receptors on isolated spine heads3,4,7-10,22-25 using 2P uncaging of glutamate. In this report we introduce a new caged compound, CDNI-GABA, that releases GABA with high quantum efficiency (0.6) and that undergoes effective 2P photolysis. Two-photon uncaging of CDNI-GABA on neurons in brain slices evoked rapid postsynaptic currents with an axial resolution of about 2 μm. This accuracy allowed high-resolution functional mapping of GABA-A receptors along the axon initial segment and the perisomatic dendritic region of CA1 pyramidal cells for the first time. Two-photon photolysis of CDNI-GABA should be a powerul tool to clarify, for example, GABAergic inhibitory effects on the ion flux through excitatory synapses, the propagation of depolarization along dendrites, and the generation of action potentials at the micrometer and even single synaptic level.

Answer: We have synthesized a photosensitive (or caged) 4-carboxymethoxy-5,7-dinitroindolinyl (CDNI) derivative of \xce\xb3-aminobutyric acid (GABA). Two-photon excitation of CDNI-GABA produced rapid activation of GABAergic currents in neurons in brain slices with an axial resolution of approximately 2 micrometers, and enabled high-resolution functional mapping of GABA-A receptors. Two-photon uncaging of GABA, the major inhibitory neurotransmitter, should allow detailed studies of receptor function and synaptic integration with subcellular precision.


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:
to report a case of recurrent idiopathic frosted branch angiitis ( fba ) successfully treated with adalimumab .
a 14-year - old otherwise healthy boy was referred to the uveitis clinic for bilateral panuveitis with diffuse retinal vascular sheathing and severe macular edema .
two years ago , a similar episode had been treated with oral prednisolone , however it was complicated by adverse psychiatric effects .
the progressive course of the condition mandated considering other therapeutic measures ; adalimumab was chosen based on its purported efficacy for treatment of childhood uveitis and a favorable safety profile .
the patient responded dramatically to a single subcutaneous injection of adalimumab without any side effect during and after injection .
to the best of our knowledge , this is the first case of idiopathic fba treated successfully with adalimumab without adjunctive steroid therapy .
frosted branch angiitis ( fba ) is a rare disease characterised by visual disturbance associated with anterior chamber and vitreous inflammation and severe sheathing of retinal vessels resembling the appearance of frosted branches of a tree .
it was originally described in a six - year - old child by ito in 1976.1 fba can be associated with ocular and systemic diseases .
cytomegalovirus retinitis , acquired immunodeficiency syndrome , and toxoplasma chorioretinitis are frequent ocular associations , while systemic lupus erythematosus , crohn 's disease , behcet s disease , large cell lymphoma , and acute lymphoblastic leukemia have been described as systemic associations.2 the idiopathic type typically occurs in young and healthy persons and is associated with good recovery of vision .
a 14-year - old boy , who was otherwise healthy , was referred to the uveitis clinic for progressive blurring of vision in both eyes since 1 month before . on examination ,
anterior segment examination revealed mild ciliary injection and anterior chamber reaction ( 2 + cells ) but no keratic precipitates or posterior synechiae .
both eyes had inflammatory reaction in the vitreous ( 2 + cells ) but there were no snow balls or snow bank formation .
fundus examination disclosed extensive retinal vascular sheathing and scattered intraretinal hemorrhages with severe macular edema in both eyes ( fig .
1 ) . systemic work - up and investigations , including a complete blood count ( cbc ) , erythrocyte sedimentation rate ( esr ) , c - reactive protein ( crp ) titer , angiotensin converting enzyme ( ace )
titer , tuberculin skin test ( tst ) , urine analysis and chest x - ray were unremarkable .
rheumatologic tests including antinuclear antibodies ( ana ) , anti double strand dna antibody ( anti ds - dna ) , rheumatic factor ( rf ) , antiphospholipid antibody , anti - neutrophil cytoplasmic antibodies ( ancas ) , and cryoglobulin assay were all negative .
blood cd4 and cd8 counts were within normal range and serology for the human immunodeficiency virus was also negative .
blood serology for possible infectious causes including herpes family viruses , i.e. herpes simplex virus ( hsv ) type 1 and 2 , varicella zoster virus ( vzv ) , cytomegalovirus ( cmv ) , and epstein - barr virus ( ebv ) , hepatitis b and c viruses , treponema , borrelia , and toxoplasma were checked .
immunoglobulin g ( igg ) levels against hsv type 2 and cmv ( but not igm ) were elevated .
we tested the aqueous specimen after an anterior chamber paracentesis to investigate the presence of deoxyribonucleic acid ( dna ) of hsv type 1 and cmv viruses .
the result of polymerase chain reaction ( pcr ) on aqueous samples was negative for both viruses . until the results of blood tests and aqueous pcr became ready , vision continued to deteriorate down to 20/1000 and 20/800 in the right and left eyes , respectively . based on the inconclusive work - up a diagnosis of idiopathic fba
the patient s parents mentioned that two years ago , for treatment of a similar condition , oral prednisolone 1 mg / kg had been commenced but soon after initiation , the patient developed severe mood changes which persisted long after discontinuation of treatment .
the progressive nature of the condition mandated considering other therapeutic measures to prevent macular scarring . due to the safety profile of anti - tumor necrosis factor ( tnf ) agents and their rapid onset of effect ,
adalimumab was considered as an alternative to conventional treatment for which the parents provided written informed consent .
a single dose of 40 mg pre - filled adalimumab ( humira , abbott laboratories , north chicago , il , usa ) was injected subcutaneously in the patient s right thigh .
no local or systemic adverse effect was noted at the time of injection or later on .
three weeks after injection , visual acuity improved to 20/200 and 20/120 in the right and left eyes , respectively .
anterior chamber and vitreous reaction decreased to 1 + cell , and vascular sheathing and macular edema resolved dramatically .
repeat fluorescein angiography and optical coherence tomography ( oct ) confirmed the improvement ( figs . 2 and 3 ) .
10 weeks after injection , visual acuity improved to 20/40 and 20/30 in the right and left eyes , respectively . in both eyes ,
clinical improvement continued up to the last visit ( 6 months after the injection ) when visual acuity reached 20/25 in both eyes with no sign of active inflammation .
fba is basically divided into three different subgroups.3 the first comprises patients affected by lymphoma and leukemia presenting with a frosted branch - like appearance in the fundus .
the second group includes patients with associated autoimmune or viral disease which can present with fba in association with the underlying disease .
the characteristic feature of this latter type is its occurrence in otherwise healthy young individuals with good recovery of vision .
clinically , there is severe sheathing of retinal vessels appearing like the frosted branches of a tree , and acute visual disturbance associated with anterior chamber and vitreous inflammation ; fluorescein angiography shows leakage from sheathed vessels without signs of occlusion or stasis.4,5 systemic steroids are the main and only suggested treatment for this condition . in our patient however , prior adverse psychiatric effects of steroid treatment encouraged us to employ another therapeutic option : adalimumab , a fully humanized monoclonal anti - tnf antibody , was chosen based on its suggested effect for treatment of refractory childhood uveitis including juvenile idiopathic arthritis.6 - 8 our patient responded dramatically to a single subcutaneous injection of adalimumab .
the improvement was rapid and long lasting and the patient did not report any side effect during follow up .
review of the literature revealed no other therapeutic option for treatment of idiopathic fba except systemic steroids . to our best knowledge
, this is the first case of idiopathic fba treated successfully with an anti - tnf agent without adjunctive steroid therapy .

Answer:
purposeto report a case of recurrent idiopathic frosted branch angiitis ( fba ) successfully treated with adalimumab.case reporta 14-year - old otherwise healthy boy was referred to the uveitis clinic for bilateral panuveitis with diffuse retinal vascular sheathing and severe macular edema .
 extensive work - up including aqueous sampling for detection of viral causes was inconclusive .
 two years ago , a similar episode had been treated with oral prednisolone , however it was complicated by adverse psychiatric effects .
 the progressive course of the condition mandated considering other therapeutic measures ; adalimumab was chosen based on its purported efficacy for treatment of childhood uveitis and a favorable safety profile .
 the patient responded dramatically to a single subcutaneous injection of adalimumab without any side effect during and after injection .
 the therapeutic effect was rapid and relatively long-lasting.conclusionto the best of our knowledge , this is the first case of idiopathic fba treated successfully with adalimumab without adjunctive steroid therapy .


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 introduction of digital technologies in clinical pathology practice could produce great benefits in the form of improved patient care , better efficiency of health services , and novel diagnostic tools . at the same time
, it is clear that these benefits can only be achieved if digital pathology solutions are carefully crafted for the clinical prerequisites . whereas low - volume and nonurgent situations such as research , teaching , and to some extent , consultations , are currently feasible with existing digital pathology systems , if digital pathology is to reach prime time status then more work is needed to enhance the suitability of the systems for clinical routine .
clinical deployment also requires solving issues such as validation mechanisms , cost - efficient digital storage , and medico - legal demands , as well as redesigning work practices for the digital era .
efforts to advance the field are taking place around the world . in the nordic countries ( sweden , denmark , norway , finland , and iceland ) , there is a particular concentration of development work towards clinical use of whole slide imaging ( wsi ) . for example , all routine histology slides are today scanned in the hospitals of linkping and kalmar and extensive digital primary review is performed , and > 60 wsi scanners have been installed in sweden to date . against this backdrop , the nordic symposium on digital pathology ( ndp ) was created to promote knowledge exchange regarding the state - of - the - art in digital pathology .
the specific focus of ndp is advances toward the clinical adoption of wsi and other digital technologies in pathology .
as these advances require a concerted effort from health care , industry , and academia , ndp is intended as a forum where professionals from all domains can meet .
the first ndp event was organized in november 2013 and attracted 125 attendees , whose feedback lead to an expanded ndp event in november 2014 as will be detailed below .
judging from the history of digitization of radiology imaging , there is reason to believe that the nordics will continue to be a forerunner in clinical use of digital pathology .
while perhaps not reflected by its regional name , ndp aims to be a venue of broad international interest where state - of - the - art in digital pathology is discussed and advanced .
nordic symposium on digital pathology symposium 2014 took place november 56 in linkping , sweden .
a total of 144 attendees gathered , of which 47% listed health care as the primary affiliation , 33% industry , and 19% academia .
the health care representatives were dominated by pathologists , but also laboratory technologists and it staff were in significant numbers .
the participants represented 14 different countries from europe , north america , and australia , with the nordic attendees being in a large majority ( 87% ) .
central to the program was a series of invited talks and a collaborative workshop on clinical deployment issues .
the contents of these sessions will be outlined in the sections below . in the science and innovation session ,
a double - blind review process was carried out by the symposium 's international program committee with 15 senior researchers in the field and this resulted in three jpi papers published alongside this editorial :  a comparative study of input devices for digital slide navigation  ( jesper molin et al . ) ,  randomspot : a web - based tool for systematic random sampling of virtual slides  ( alexander wright et al . ) , and  histopathology in three - dimensional : from three - dimensional reconstruction to multi - stain and multi - modal analysis
in addition , the ndp included an industrial exhibition consisting 13 vendors , ranging from large multinationals to recent startups , showing everything from wsi scanners through enterprise image management to desktop electron microscopy .
figure 1 shows a session snapshot and the program details are available at the npd website http://www.liu.se/ndp?l=en .
a key part of the ndp program was the workshop discussing clinical adoption of digital pathology .
the workshop was organized as an open floor discussion where broad participation was encouraged and also achieved . as an input to the discussion
, a survey was distributed among the health care attendees in advance of the symposium .
some results from this survey will be presented next as it paints an interesting picture of the attitude toward digital pathology in nordic health care .
it must be noted that the respondents of the survey represents an extremely biased selection among the pathology community .
since only ndp participants were asked , this means that respondents are likely to be among the most positive to digital pathology and also among the most experienced .
there is also strong geographical dominance from the nordics and in particular sweden . of 74
it is likely that the pathologist dominance were even higher for some questions that require deep knowledge of clinical practice .
role distribution of survey respondents the survey first asked :  today , to what degree do you use digital images of histology slides in your practice ? ( in % of all histology cases . )  the results are shown in figure 3 , showing moderate levels of adoption but no use in about 50% of respondents .
another bias to note for these questions is that several people from the same institution may have responded . since the most digitized sites kalmar and linkping had several attendees , these numbers are likely to represent higher usage than numbers on a per site basis .
current use of digital pathology among survey respondents the same question was asked for the predicted situation at the end of 2016 , shown in figure 4 , showing significant optimism for near - future use of digital pathology . predicted use of digital pathology at the end of 2016 the respondents
were also asked to judge the impact of digitization :  what effect do you foresee that digital pathology will have compared to traditional microscope practice , with regards to the following areas ?  the impact grading was given in a five - point scale ,
major negativeminor negative    status quo    minor positive    major positive .
the assessments with regards to pathologist work are in figure 5 whereas other laboratory aspects are in figure 6 and overall impact in figure 7 . foreseen impact of digitization with regards to pathologist 's work foreseen impact of digitization with regards to laboratory aspects foreseen impact of digitization with regards to overall effects broadly , these responses indicate a very positive attitude toward digital pathology in terms of its effects on pathologist and laboratory working .
however , more negative responses were received in the effect on pathologists efficiency ( time per case and speed of slide navigation ) as well as perceived delays in slide arrival from the laboratory until starting review .
overall effects of digitization were seen as very positive , especially for the quality of care .
finally , the respondents also were asked to state the three main barriers for adoption of digital pathology in their clinical practice .
it was clear that the cost of implementation is a major issue ; 79% of the responses mentioned lack of sufficient funds as a barrier .
technology limitations were listed in 71% of the responses , some referring to insufficient performance of commercial solutions and some referring to lacking it infrastructure in their organization . a conservative attitude among colleagues
other responses concerned lack of organizational engagement at local , national and international levels to develop protocols , work practices , and standards .
after the survey results had been presented , a guided discussion between all participants took place .
advanced digital pathology implementation efforts were reported by many contributors , either established ( e.g. skne , linkping ) or in planning ( e.g. , gothenburg , karolinska / stockholm , oslo , copenhagen ) .
the planned use cases covered similar areas such as retrieving archived cases , presenting at multi - disciplinary meetings , obtaining second opinions ( either for individual cases or to share work between institutions ) .
digital pathology was seen by many contributors as a key enabler of higher quality pathology services , by increasing specialist reporting of cases or supporting and supporting colleagues across distances .
those who had implemented digital pathology on a large scale were positive about the effects it had on workflow and reported no untoward delay in slide arrival caused by the extra step of scanning ( in fact , one pointed out that the cases arrived in a more continuous flow , rather than the batches of glass slides normally received ) .
several contributors ( linkping , skne , toronto ) had experience of working with moderate or large volumes of the digital work .
fatigue using dp systems was mentioned by a few , possibly a combination of older less effective slide viewing software and the known effect of computer displays on eye fatigue .
several experienced commenters pointed out that fatigue was often an issue with the microscope and that digital pathology offered ergonomic benefits which could be beneficial in the long term for the pathologist 's experience .
laboratories produce a lot of glass slides , and wsis produce large amounts of storage space .
it was felt that data storage was very often raised as a concern by it departments involved in discussions about digital pathology implementations .
some contributors pointed out that projections of hundreds of terabytes of image data per year , while realistic for 100% digital practice , may serve to inhibit pathologists and it departments from trying the technology , and that in fact to start going digital - only a modest storage capacity of a few terabytes is needed .
it contributors pointed out that mature information lifecycle management systems for digital pathology had yet to appear ( some contributors reported being charged excessive monthly costs for even small amounts of data ) , but it was likely that tiered storage systems would ameliorate the daunting costs associated with large amounts of live online storage , as would the constant reduction in price per terabyte of storage media .
some discussion around how long digital images should be kept for and what latency before image retrieval might be tolerated revealed that several contributors had envisaged such tiered data arrangements would be needed .
centers with mature or second - generation digital pathology systems often had it staff who understood well the complexities of wsi data , and well - integrated systems .
experienced users re - emphasized the need for digital pathology to be supported by knowledgeable and ( preferably ) designated it staff .
standards were mentioned by only a few contributors - the it staff , who expressed surprise at the lack of standardization of digital pathology image formats and interoperability , and those pathologists on their second generation of scanners who had experienced incompatibility between two different vendors products ( e.g. in viewers or in image analysis algorithms ) .
some audience members had experience of the last digital revolution in medical imaging ( in radiology ) and saw many parallels in the it needs , questions about validation / safety and clinical acceptance of the technology .
the room was understandably full of those keen to adopt digital pathology , many of whom reported colleagues with more conservative attitudes .
some of the objections were seen , however , as entirely justifiable ( e.g. concerns over speed of diagnosis and diagnostic accuracy with digital systems ) and many in the room agreed that these were issues that needed to be addressed . for successful implementations ,
the need for champions in each department was mentioned , as well as the value in immersing trainees in a digital working pattern from an early stage .
wiser ( and older ) heads pointed out the benefits of actively seeking out sceptics and involving them in digitization projects .
dr . andrew evans from the university health network , toronto described a long - standing program of digitization including telepathology and wsi in a university hospital network .
he provided a very detailed description of the assiduous planning involved in digital pathology adoption and his experiences of involving the entire department in projects .
metin gurcan of ohio state university spoke about his work in image analysis and computer aided diagnosis , introducing many parallels from radiological imaging and emphasizing the importance of pathologist - computer scientist partnerships and validation in such work .
jan baak from stavanger university hospital gave an expansive talk on his long career in pathology imaging , especially speaking about his role in the prognostication of breast cancer with morphology and image analysis , emphasizing the ongoing value of good pathological assessment even in a genomic era .
dr . sten thorstenson from linkping university hospital explained his long experience of digital pathology at kalmar and linkping , starting at a time when a terabyte really was a large amount of data .
after 9 years he reports being entirely comfortable working digitally and has been reporting 100% from home for almost a year now without access to a microscope or physical slides .
derek magee from the university of leeds gave an overview of his work in image analysis research .
a focus area has been digital three - dimensional pathology , and in particular tackling the inherent challenges of the slide registration , color normalization , and histology - radiology correlation .
thomas miliander from vrmland county council , sweden , presented this health - care provider 's strategy for imaging it infrastructure .
the approach taken is an enterprise image management backbone for all medical images , relying on standards for tight integrations with other information systems , a context into which now also wsi is entering .
johan lundin from the institute for molecular medicine finland , helsinki , provided an overview of his group 's work in digital pathology .
the portfolio presented spanned from web and touch - enabled wsi viewing applications to low - cost handheld microscopes utilizing smartphone camera components . in a special session ,
elin kindberg of sectra presented preliminary results from a national swedish effort to investigate key medico - legal issues arising when deploying digital pathology . regarding access to swedish patient data outside of sweden
the legal situation is clear that this is possible provided those appropriate security measures are taken .
legal directions regarding whether all wsi data must be stored does not , however , exist ; the swedish law only mandates  good and safe health care .
the conclusion is that the pathology profession needs to define what the legal mandate means in this case .
the swedish pathologist society is now finalizing an official guideline document describing different possible paths , all legal , and all with different advantages and drawbacks .
the 2 ndp spanned across many areas of interest with regards to the emerging use of wsi and related it tools in clinical routine .
feedback from attendees indicates that this sharing of knowledge and experiences across organizations , disciplines , and sectors is an important catalyst for development of best practices and overall progress .
organizing ndp 2014 has been a very rewarding experience , and we welcome attendees from all over the globe to future gatherings of this group .

Answer:
techniques for digital pathology are envisioned to provide great benefits in clinical practice , but experiences also show that solutions must be carefully crafted .
 the nordic countries are far along the path toward the use of whole - slide imaging in clinical routine . the nordic symposium on digital pathology ( ndp )
 was created to promote knowledge exchange in this area , between stakeholders in health care , industry , and academia .
 this article is a summary of the ndp 2014 symposium , including conclusions from a workshop on clinical adoption of digital pathology among the 144 attendees .


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:
langerhans ' cell histiocytosis ( lch ) is a proliferative disease characterized by monoclonal proliferation and the infiltration of organs with langerhans ' cells .
several organ systems may be involved in lch including the lungs , bone , skin , pituitary gland , liver , lymph nodes , and thyroid .
localized forms of lch in bone have been referred to as eosinophilic granuloma since lichtenstein first described them in 1940 .
the term " pulmonary langerhans ' cell histiocytosis ( plch ) " was first coined by farinacci in 1951   and refers to disease in adults that affects the lungs , either in isolation or in addition to other organ systems .
multi - systemic variants of this disease are known by a variety of names , including systemic histiocytosis x , letterer - siwe disease , and hand - schuller - christian disease . to avoid confusion ,
the histiocyte society has established a simplified classification system . according to this system , plch is a disease in adults that affects the lungs , either in isolation or in addition to other organ systems .
the most common findings on high - resolution computed tomography ( hrct ) of the chest are multiple nodular and cystic changes , which occur predominantly in the middle and upper lobes .
nodular lesions are predominant in the early stage of plch and progress to cystic lesions in later stages of the disease . in korea , multiple cystic lesions are the main radiological findings of plch , and no cases with multiple nodular lesions without cysts have been reported . here
, we report a case of plch with multiple nodules without cysts throughout the lungs .
a 31-year - old male was admitted to our hospital for a cough and exertional dyspnea , which had been present for 2 months . he had no hypertension , tuberculosis , or diabetes , and no history of surgery , medication , or travel .
his vital signs were blood pressure 120/80 mmhg , pulse 84/minites , respiration rate 20/minites , and body temperature 37.2. physical examination of the head and neck revealed no palpable cervical lymph nodes or masses and no neck vein engorgement .
auscultation of the chest revealed a regular heart beat with no murmurs and clear breath sounds with no crackles or wheezing .
laboratory examination indicated a white blood count of 10,310/mm , hemoglobin concentration of 16.0 g / dl , and platelet count of 202,000/l , and the chemistry was unremarkable .
arterial blood gas analysis revealed a ph of 7.455 , pao2 99.1 mmhg , paco2 38.2 mmhg , hco3 27 mmol / l , and 98% o2 saturation .
the results of the pulmonary function test were forced vital capacity ( fvc ) 5.46 l / minites ( 105% of predicted ) , forced expiratory volume in 1 second ( fev1 ) 4.59 l / minites ( 110% of predicted ) , and fev1/fvc 84% .
we performed fiber optic bronchoscopy for bronchoalveolar lavage and observed no abnormal findings in the gram stain or culture , acid - fast bacillus stain or culture , tuberculosis - pcr , or cytology .
the chest ct revealed variable - sized nodules with peribronchiolar or centrilobular distribution , some of which revealed thick - walled cavitary change ( fig .
the differential diagnosis based on the chest ct findings was that the pulmonary nodules represented hematogenous metastasis .
histologically , multiple nodules showed an infiltration of eosinophils , lymphocytes , and langerhans ' cells ( fig .
treatment consisted only of smoking cessation , and a chest radiograph 4 months later indicated that the nodules had decreased in size .
after 15 months , we observed that the symptoms had improved further , and a follow - up chest radiograph and hrct indicated that the multiple nodules had disappeared ( fig .
this case involved a young male who currently smoked and had multiple pulmonary nodules , which were suspicious of metastasis .
plch is a rare disorder found in only 5% of biopsy - confirmed interstitial lung disease .
reviewed 102 cases with histopathologically confirmed plch drawn from a group with a mean age of 40.3 years and a 1 : 1.5 ratio of males to females and found that 95% of the cases involved smokers .
the only consistent epidemiologic association is cigarette smoking , which is involved in the overwhelming majority ( > 90% ) of cases .
several hypotheses have been proposed to explain the association between cigarette smoking and plch . according to one ,
cigarette smoke induces the secretion of bombesin - like peptides from neuroendocrine cells in the lungs .
these peptides may have an important role in mediating lung injury and consequently induce lung fibrosis .
other components of cigarette smoke , such as tobacco glycoprotein , have also been implicated in the pathogenesis of plch .
nevertheless , plch occurs in a very small percentage of smokers , so genetic or environmental factors likely contribute to the development of this disease .
a young male who currently smoked complained of a cough and exertional dyspnea , common clinical features of plch ; however , the radiological findings did not support a diagnosis of plch .
hrct of the chest is a useful , sensitive tool in the diagnosis of plch .
the combination of diffuse , irregularly shaped cystic spaces with small peribronchiolar nodular opacities , predominantly in the middle and upper lobes , is highly suggestive of plch [ 6 - 8,13 ] .
when these features are present on hrct , they allow the clinician to make a diagnosis of plch without a lung biopsy .
the lung cysts of plch are often less than 20 mm in diameter and typically have thin walls ( < 1 mm ) [ 6 - 8 ] . the frequency of cystic change reflects the timing of imaging during the course of the disease [ 1,6 - 8 ] . in the early stages ,
the most common finding is nodular change , whereas in the later stages , cystic change and fibrosis predominate [ 6 - 8 ] .
based on the radiological staging , this case represents an early stage of plch comprised of nodular lesions only without cystic change .
this finding is rare ; only one other case of plch with multiple cavitating pulmonary nodules has been reported , although several cases of plch presenting as a solitary pulmonary nodule have been reported worldwide .
none of these cases progressed to a more severe stage , such as cystic change or reduced pulmonary function .
brauner et al .   reported two cases of plch in which only nodules were present : one progressed to cystic change and the nodular lesion disappeared in the other .
it is thought that predominantly nodular lesions in plch appear early in the reversible state of the disease . in korea ,
a number of cases of plch have been reported based on variable radiological findings , including multiple cysts and a combination of nodules and cysts . however , no case involving only nodular lesions has been reported .
atypical radiological findings as in this case need to be followed to determine whether sarcoidosis , pneumoconiosis , military tuberculosis , hypersensitivity pneumonitis , or metastatic lung nodules are present .
the confirmative diagnostic tool is a pathological examination of a lung biopsy . in this case ,
an open lung biopsy was performed , which resulted in the diagnosis of plch based on positive staining for s-100 protein .
the only treatment was smoking cessation , and clinical and radiological improvement was observed 15 months later .
here , we report a case of early stage plch in a young male that had atypical radiological features , which consisted of variable - sized nodules only without cystic changes .

Answer:
a 31-year - old man presented with a dry cough and exertional dyspnea .
 the chest x - ray showed multiple nodular opacities throughout the entire lung field .
 chest computed tomography ( ct ) revealed variable - sized nodules with a peribronchiolar or centrilobular distribution , some of which revealed thick - walled cavitary change . based on the chest ct findings , it was initially assumed that metastatic lung nodules with hematogenous spread were present ; therefore , we performed an open lung biopsy . on microscopic examination ,
 several compact cellular interstitial infiltrates composed of langerhans ' cells , eosinophils , and lymphocytes were observed .
 immunochemically , the langerhans ' cells showed strong cytoplasmic staining for s-100 protein .
 based on these findings , the patient was diagnosed with langerhans ' cell histiocytosis of the lung .
 high - resolution ct of the chest is a useful , sensitive tool in the diagnosis of pulmonary langerhans ' cell histiocytosis ( plch ) .
 a typical radiologic finding of plch is irregularly shaped cysts .
 the radiological finding in this case of nodular opacities throughout the lung fields only without cysts is rare in plch .
 we report a case of plch with atypical multiple nodules mimicking hematogenous metastatic lung nodules .