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:
perforation of the biliary system occurs
 most frequently in the gallbladder , usually associated with ( and complicating
 upto 10% cases of ) acute cholecystitis .
perforation of the extrahepatic biliary
 tree is a rare entity , accounting for less than 10% of intraperitoneal biliary
 rupture .
bile duct perforation is most commonly described in infants related to congenital
 biliary system anomalies .
aetiology in the adult is commonly attributable to
 intramural infection , necrosis of the wall of the bile duct secondary to
 thrombosis , increased intraductal pressure secondary to obstruction , cirrhosis ,
 and direct erosion by calculi .
overall , 70% of cases are related to calculi
 . the incidence of biliary tract disease during pregnancy ranges from 0.050.3% . despite these apparent low
 figures , complications from gallstones
represent the most common general surgical condition
 requiring surgical intervention , second only to appendicitis .
indications for intervention of gallstones during pregnancy
 include obstructive jaundice , acute cholecystitis , or pancreatitis failing
 medical management .
we present the case of a young woman diagnosed with
 gallstones in late pregnancy , complicated by acute gallstone pancreatitis and
 subsequently spontaneous common bile duct perforation .
a twenty - year - old primigravida woman was
 planned for elective caesarean section due to breech presentation .
the patient
 had a past medical history of -thalassemia trait , but was not
 normally on regular medication .
her mother had previously undergone a
 cholecystectomy for gallstones . at 34 weeks gestation , she presented
 acutely with a two - week history of worsening abdominal pain localised to the
 epigastric region , associated with vomiting . on examination ,
blood results revealed raised inflammatory markers ( wbc 14.4 [ 4.011.0 ] ,
 neutrophils 11.9 [ 2.07.5 ] , crp 60
 [ 07.5 ] ) and evidence of pancreatitis ( amylase 1369
iu / l [ 36128 ] ) , mildly
 raised bilirubin ( 24 mol / l [ 020 ] ) and raised alkaline phosphatase ( 183
an abdominal ultrasound revealed multiple small gallstones and a
 thickened gallbladder wall , but no evidence of a dilated intra or extrahepatic
 biliary system .
the patient was treated conservatively , rapidly improved , and liver function tests
 normalised .
an emergency caesarean
 section was performed and a term baby delivered , but no obvious cause was found
 to explain her clinical condition .
the following day her clinical condition worsened , with progressive abdominal pain
 and a metabolic acidosis .
she required aggressive resuscitation , inotropic , and ventilatory support and was ,
 therefore , admitted to the intensive care unit .
a computed tomography ( ct )
 revealed extensive free peritoneal fluid and gas of which the aetiology was not
 apparent .
the patient underwent a prompt laparotomy and was found to have
 generalised biliary peritonitis .
the gallbladder was intact but a 2 mm
 perforation was found on the anterior surface of a dilated common
 bile duct ( 12 mm ) . on table
cholangiography suggested obstruction of the distal
 common bile duct caused by a 5 mm gallstone impacted within the distal common
 bile duct .

the calculus was removed , and the duct was repaired over a t - tube .
a t - tube cholangiogram was performed
 after 4 weeks , and the tube was uneventfully removed ( figure 1 ) .
although the pathogenesis of spontaneous biliary perforation is poorly understood ,
 recognised mechanisms include the following : calculous perforation at the site
 of impaction ; calculous erosion without impaction ; increased canalicular
 pressure due to obstruction by tumour , stone , or spasm of the sphincter of
 oddi ; intramural infection ; mural vessel infarction leading to mural necrosis ;
 or rupture of a biliary tract anomaly such as cyst or diverticulum .
thus ,
 because perforation of the biliary system is a recognised complication of
 cholelithiasis , the diagnosis should be suspected if a perihepatic abscess or
 peritonitis is combined with biliary stone disease . as early as 1882 , freeland   reported the first case of extrahepatic biliary system rupture in an adult ( diagnosed at autopsy ) , an entity that was
 subsequently first described in pregnancy by piotrowski et al .   over a
 century later . since this time ,
very few cases of spontaneous common bile duct
 perforation in adults have been reported in the literature , with cases
 occurring during pregnancy being even more scarce .
the importance of this clinical
 scenario lies in the potential serious morbidity and not infrequent mortality
 associated with missed biliary system perforation .
petrozza
 et al .   described two cases of gallbladder perforation due to cholelithiasis in
 the early postpartum period .
both cases presented a diagnostic dilemma , and it
 was concluded that a history of cholelithiasis in a patient with persistent
 intra - abdominal symptoms in the postpartum period must alert to prompt
 investigation and early management .
,
 one patient was found to have suffered gallbladder rupture as a result of
 cholecystitis , and in the second , a common bile duct perforation was found at
 laparotomy with no obvious precipitating cause .
.   also drew
 attention to the similarity of symptoms of gallbladder disease in pregnancy to
 mild pre - eclampsia , having in common hypertension , epigastric pain , and mildly
 deranged liver function tests .
these cases highlight the importance of
 recognising the possibility of delayed diagnosis of cholelithiasis as a result
 of nonspecific abdominal symptoms during pregnancy and indicate early
 investigation and treatment in order to reduce serious morbidity .
.
 block and kelly   reported the optimum time for surgical management of
 gallstone pancreatitis to be in the second trimester or early postpartum
 period , in order to minimise maternal / fetal mortality and recurrent
 pancreatitis .
unfortunately , in those women presenting
 late in pregnancy ( as in the case described ) , the balance of risk favours
 watchful waiting until after delivery followed by elective cholecystectomy .
 certainly , this risks early recurrence of acute pancreatitis , as well as rare but severe
 consequences such as biliary peritonitis .
 whether an early endoscopic retrograde cholangiopancreaticography ( ercp )
 and sphincterotomy in those cases presenting with gallstone pancreatitis can be
 an acceptable temporary preventive measure is unclear , but undertaking ercp is
 not without risk , and the potential risks should be considered carefully in
 individual cases . in this particular case ,

it is impossible to know whether the eroding calculus had been present during the
 initial episode of pancreatitis .
magnetic resonance scanning is a commonly used
 imaging modality in obstetrics , considered to be safe and avoiding the use of
 ionising radiation .
therefore , magnetic resonance cholangiopancreatography
 ( mrcp ) would have been a reasonable next investigation during this patient s
 initial presentation , and if a ductal stone had been revealed , then the indication
 for ercp may have been clearer .
on the other hand , neonatal and postnatal
 care of babies born early have progressed significantly , suggesting the
 possibility of induction of labour perhaps at 3638 weeks
 gestation in severely symptomatic or high - risk patients .
of course , every case
 must be considered individually , taking into account maternal and fetal
 history and health .

Answer:
spontaneous perforation of the extrahepatic biliary system is a rare presentation of ductal stones .
 we report the case of a twenty - year - old woman presenting at term with biliary peritonitis caused by common bile duct ( cbd ) perforation due to an impacted stone in the distal common bile duct .
 the patient had suffered a single herald episode of acute gallstone pancreatitis during the third trimester .
 the patient underwent an emergency laparotomy , bile duct exploration , and removal of the ductal stone .
 the postoperative course was uneventful .


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 standard management for muscle - invasive transitional cell carcinoma ( tcc ) and non - muscle - invasive tcc of bladder with a high risk of progression is radical cystectomy with pelvic lymph node dissection .
orthotopic neobladder ( onb ) substitution is an accepted form of urinary diversion after radical cystectomy with a better quality of life as compared with cutaneous urinary diversion .
there is a possibility of urethral recurrence after onb substitution , compromising its functional integrity .
the reported recurrence rate of urethra after radical cystectomy has a wide variation and ranges from 0.5% to 18% . in initial studies ,
prostatic involvement was considered as a significant prognosticator for urethral recurrence , but later on it was shown that despite a positive endoscopic biopsy from the prostatic urethra , if the resected margin of the urethra on frozen section analysis ( fsa ) was negative , then the urethral recurrence is unlikely even after 10 years of follow - up .
there is paucity of data on the robustness of intra - operative fsa , influencing the decision of urinary diversion .
more often than not , the yield of fsa is lower than expected , and , in a majority of cases , it seems to be an unnecessary step .
it is interesting to see that even a positive urethral margin on fsa does not predict the recurrence of tcc at the urethral stump .
this raises an important issue of performing a step as a routine when it may not be necessary .
we analyzed our data to assess the need for fsa in patients of radical cystectomy planned for onb .
for this institutional ethics board approved study , data on radical cystectomy performed between january 2000 and june 2013 were retrieved from the hospital information system and internal data management source of our center .
a total of 233 radical cystectomies were performed during the study period . of these ,
, fsa was performed for presence or absence of malignancy at the urethra on the patient side .
based on the low yield of fsa , after 2010 , this step was not performed as a routine and only those patients who had visible growth at the bladder neck had fsa . for statistical analyses ,
patients were grouped into three groups , i.e. patients with fsa and positive margin , patients with fsa but negative margin and those in whom fsa was not performed .
pathological characteristics of these groups were compared for local staging and presence or absence of carcinoma in situ . a contrast - enhanced computed tomography ( cect )
imaging parameters like hydroureteronephrosis , tumor size at the time of presentation and site of the bladder tumor in relation to the bladder neck were assessed .
location of the tumor in relation to the bladder neck and trigone on cect was matched with the findings on the cut - open specimen .
patients were followed - up every 4 months with ultrasonography , serum creatinine , lower urinary tract symptoms , uroflowmetry , post - void residue and venous blood gas analysis .
survival curves for patients whose fsa was negative and patients who did not have fsa were compared with the log rank test .
binary logistic regression analysis was performed to analyze the effect of imaging parameters on the status of the urethral margin .
all the statistical analyses were performed using spss 16 ( chicago , il , usa ) .
survival curves for patients whose fsa was negative and patients who did not have fsa were compared with the log rank test .
binary logistic regression analysis was performed to analyze the effect of imaging parameters on the status of the urethral margin .
all the statistical analyses were performed using spss 16 ( chicago , il , usa ) .
survival curves for patients whose fsa was negative and patients who did not have fsa were compared with the log rank test .
binary logistic regression analysis was performed to analyze the effect of imaging parameters on the status of the urethral margin .
all the statistical analyses were performed using spss 16 ( chicago , il , usa ) .
the mean age of 151 patients who were planned for onb was 56.3  10.7 years .
of those 109 patients , only three ( 2.7% ) patients had a positive urethral margin .
two of them had ileal conduit diversion and one patient , after having a negative biopsy on the second fsa , had onb .
although none of the factors , i.e. hydroureteronephrosis , tumor size and site , were found to be significant for predicting urethral margin status , all three patients with a positive urethral margin had tumor encroaching the bladder neck [ figure 1 ] .
all the patients with a positive urethral margin died of cancer at a mean follow up of 29.33  18.3 months , but none had urethral recurrence till the time of death .
patients who died of cancer had pelvic and/or distant metastasis . pathological characteristics of the patients according to the urethral margin status outcome of the patients according to the frozen section analysis ( fsa ) of the urethral margin one of the patients with a positive urethral margin who had tumor involving the bladder neck ( blue solid arrow ) overall , 34/151 ( 22.5% ) patients had growth at the bladder neck on cect . of these , six tumors were actually found to be away from the bladder neck on the cut - open specimen .
[ figure 2 , table 3 ] the false - positive report of bladder neck involvement on cect was 18% , ( six of 34 cases ) .
therefore , only 28/138 ( 21.5% ) patients had growth at the bladder neck [ table 3 ] .
of these 28 patients , three ( 10.7% ) had a positive urethral margin and all these three patients had tumor involving the bladder neck .
tumor involving the bladder neck on the contrast - enhanced computed tomography scan was found to be away from the bladder neck in the cut - opened specimen ( white solid arrow ) comparative results of bladder neck involvement found on cect and during naked eye examination in the surgical specimen regarding association of the urethral margin with the involvement of the prostate , it was found that of 141 male patients , 10 ( 7% ) had their prostate involved but none had a positive urethral margin [ table 4 ] .
similarly , two male patients who had a positive urethral margin had no prostatic involvement .
location of the tumor at the bladder neck did not correlate with the involvement of the prostate ( p = 0.983 ) [ table 4 ] .
relationship between location of the tumor and the involvement of the prostate gland ( n=128 ) the 1- and 5-year overall survival of patients with negative fsa were 91.5% ( 95% ci , 8593.5 ) and 79% ( 95% ci , 7284% ) , and of those in whom fsa was not performed were 93% ( 95% ci , 8695% ) and 82% ( 95% ci , 7489% ) .
[ figure 3 ] the mean follow - up times were 46.3  25.1 months and 36  9.3 months for the frozen section negative and not sent groups , respectively .
none of the patients without fsa ( 42 ) had urethral recurrence at a mean follow - up of 36  9.3 months .
meir survival curve with log rank test comparing survival in patients with negative urethral margin and in patients in whom frozen was not sent only two patients had recurrence in the penile urethra : one patient after 6 years and the other patient 2 years following onb . in both the cases ,
the urethral biopsy was positive for malignancy but the neo bladder urethral junction was normal .
the gold standard treatment for muscle - invasive or recurrent transitional carcinoma of the urinary bladder is radical cystectomy with urinary diversion . among the various kinds of urinary diversions ,
onb substitution provides the most natural way to void , with a relatively better quality of life .
the whole purpose of using an external sphincter as a continent mechanism for onb would be defeated if there is recurrence in the urethra .
therefore , it is a standard practice to send the urethral margin for fsa before performing onb to ensure that the urethral margin is negative . the reported rate of urethral recurrence after radical cystectomy has a wide variation , ranging from 0.5% to 18% .
as recurrence at the urethral stump is known even after having a negative margin , it seems likely that the reason for recurrence is not the status of margin assessed by the available means . according to early reports ,
the most consistent risk factor in men for predicting urethral recurrence was the involvement of the prostate .
although urethral recurrence was not common in patients with prostatic urethral involvement , prostatic ductal and stromal involvement were associated with the urethral recurrence , ranging from 10% to 67% .
similarly , women with tumors located at the bladder neck or involving the anterior vaginal wall are at a higher risk for urethral recurrence .
later on , onb substitution was perfromed even in patients who had involvement of the prostatic urethra ( confirmed on endoscopic biopsy ) , provided the fsa showed a negative urethral margin .
after a minimum follow - up of 10 years , none of the patients had urethral recurrence . in another study of a similar kind , the positive and negative predictive values of the prostatic urethral biopsy prior to cystectomy were 12% and 99.9% , respectively .
they concluded that presence of tumor in the prostatic urethra prior to cystectomy would not preclude orthotopic neobladder substitution if the urethral frozen section is negative .
following these studies , intraoperative frozen section biopsy of the urethral margin became the pre - requisite for an onb , disregarding the status of prostatic involvement .
interestingly , that the rate of urethral recurrence in patient undergoing onb has been found to be low .
although these studies are retrospective in nature , where bias of choosing a case with better tumor characteristics could be the reason , the inexplicable protective effect of onb against recurrence at the urethral margin is quite evident .
published their series and concluded that patients with onb have a lower risk of urethral recurrence than those who had cutaneous urinary diversion for tcc urinary bladder .
this protective effect of onb for urethral recurrence was also demonstrated by stein et al .
although one would argue against not performing fsa , one needs to assess the overall impact of fsa in terms of decision making for or against the onb .
urethral recurrences have also been reported with the negative urethral margin , the incidence of which has been described to range from 0.9% to 2.8% . in one series , two of 13 patients with positive fsa had urethra recurrence as opposed to 13 recurrences in 222 patients who had negative fsa .
therefore , the urethral margin status failed to accurately predict recurrence at the urethral stump . in the present study too , we had a very low yield of frozen section biopsy , wherein we had only 2.7% of positive fsa .
all three patients died of their disease , but none had urethral recurrence at the time of death . among the survivors also , we had only two urethral recurrences at the mid penile urethra , and both the patients had negative fsa as well .
looking at the recurrence rate of less than 3% at the urethral stump and low positive predictive value of the frozen section , should we be performing fsa in all the patients ?
moreover , an overall survival in patients where frozen was not sent was not different from those in whom frozen was sent and had a negative urethral margin .
interestingly , in our study , although the location and size of the tumor and hydroureteronephrosis did not predict the status of the urethral margin , three patients who did have a positive urethral margin had tumors located at the bladder neck . in our experience ,
carcinoma in situ ( cis ) changes are not found as frequently as reported in the literature ; moreover , normal - looking mucosa on cystoscopy is unlikely to have cis changes .
none of the patients who had tumor away from the bladder neck showed a positive margin , and about 77.5% of our patients had growth away from the bladder neck .
the cut - section of the specimen immediately after the cystectomy is a useful way to determine the location of the growth at the neck , as six of 34 ( 18% ) cases had a false - positive report on cect scan .
involvement of the prostate in the radical cystectomy specimen in the present study was just 7% , as against 17% in one of the largest series on radical cystectomy .
none of the patients with prostatic involvement in the present series had a positive urethral margin , which contradicts the theory of synchronous involvement of the urethra .
visual impression of the specimen to determine the encroachment of tumor to the bladder neck , similar to the one we apply during partial nephrectomy , could be helpful in deciding against sending a routine frozen section
. limitations of the study are relatively less number of patients with positive urethral margin and relatively short follow - up of those in whom we did not send the frozen section .
this study questions the ubiquity of performing a step that is unlikely to help in decision making . in the majority of cases
, fsa seems to be an unnecessary step and mere visual impression of the tumor and urethra could be helpful in deciding about sending the urethral margin for fsa .
only patients who have growth located at the bladder neck on the cut - open specimen should have fsa .

Answer:
introduction : this study was aimed at analyzing the need for routine use of frozen section analysis ( fsa ) before performing orthotopic neobladder ( onb ) after radical cystectomy for carcinoma urinary bladder.materials and methods : a total of 233 patients underwent radical cystectomy from january 2000 to june 2013 .
 of these , 151 ( 65.6% ) patients were planned for onb . in the initial 109 ( 72% ) patients ,
 fsa of urethral margin was performed , but , in the subsequent 42 ( 28% ) patients , frozen section of urethral margin was not sent .
 impact of hydroureteronephrosis , tumor size and location of tumor in relation to the bladder neck on the status of the urethral margin was analyzed.results:only three of the 109 ( 2.7% ) patients had a positive urethral margin .
 two of them had ileal conduit and one , after negative re - resection , had onb .
 although none of the factors was found to be significant , all three patients with a positive urethral margin had growth at the bladder neck and died of cancer at a mean follow up of 29.33  18.3 months , without urethral recurrence . among the negative fsa ( 106 ) , two patients had recurrence in the penile urethra .
 the mean follow - up was 46.3  25.1 months .
 none of the patients without fsa ( 42 ) had urethral recurrence at the mean follow - up of 36  9.3 months .
 of the 28 patients who had their growth located at the bladder neck , three had positive fsa , while none with growth away from the bladder neck had positive fsa.conclusion:routine fsa of the urethra before performing onb can be avoided in those patients where the tumor does not reach the bladder neck .


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:
Permuting Diels-Alder and Robinson Annulation Stereopatterns

Paper sections:
Introduction

Synthetic planning directed to conjugated octalones, of the type 1, traditionally tends to center around enolate and enol based progressions inherent in the expression "Robinson Annulation" (RA, see eq. 1).1,2,3 By contrast, nonconjugated octalone systems of the type 2 are perceived as likely to arise from a Diels-Alder based cycloaddition logic (DA, eq. 2).4,5,6,7
(1)
(2)

Not surprisingly, these widely used synthetic platforms lead to differing biases in diastereoselection. For instance, consider the consequences of these modalities for orchestrating a 1,4 stereorelationship in a bicyclic product arising from two kinds of cyclohexene substrates – an enolate (3) and an enone (5). In the R A m o d e , diastereofacial induction tends to be stereoelectronically, rather than sterically, driven for the RA progression.8 Thus, if enolate alkylation occurs in the preferred axial sense, with the resident C5 group (asterisk) equatorial, formation of an "anti product," of the type 4 would be favored.9,10 By contrast, in the DA modality, preferred combination of the DA diene with 5 would tend to occur anti to the R group, leading to a "syn" type product (6).11
(3)
(4)

These differing stereopatterns are also associated with strikingly different displays of the key functional groups (olefin and ketone) in the bicyclic products (compare octalones 1 and 2). Given this situation, we addressed the question as to whether the conventional structural and diastereoselection tendencies can be exploited such that a DA "stereopattern" might be transmitted to a typical RA type product.

Recently, we described a somewhat fortuitous discovery, wherein the double bond of a Diels-Alder derived octalone of the type 7 can be isomerized under mediation by silica gel to afford 8 (Scheme 1).12,13 The latter type of structure is easily seen to be a double bond isomer of a standard Diels-Alder cycloaddition product. It could well be anticipated that Saegusa-Ito-type oxidation14,15 of 8 would give rise to 9, in which a DA stereochemical pattern is ensconced in an RA functional group arrangement (i.e. the expected "wild-type" RA stereomotif would be that shown in 10).

Attention has already been drawn16 to the potential value of pattern recognition analysis (PRA) as a resource in the planning of the synthesis of complex targets. While the compelling logic of prioritized strategic bond disconnection, advanced by Corey and associates many years ago,17,18 still lies at the heart of contemporary retrosynthetic analysis, PRA, which seeks out identifiable holistic substructural domains, may provide a complementary venue for forward planning.16 Thus, the question we posed above, concerning the permutability of the diastereoselectivity biases of these key reaction types, has the potential to offer new avenues for synthetic planning, particularly in subtle issues of stereochemistry (vide infra, syntheses of carissone19 and of the reported structure of cosmosoic acid20).

Results and Discussion

As shown in Scheme 2, we began our inquiry by demonstrating how two mainstay products of classical RA-based strategies, the Hajos–Parrish ketone (13)21 and the Wieland–Miescher ketone (14),22 could be synthesized in quite reasonable overall yields from the easily available, appropriate α-methylcyclenones.23,24 Of course, in the particular cases of 13 and 14, there were no issues of relative stereochemistry to be addressed. Though we have not yet pursued the matter, enantioselectivity could, in principle, be realized from a catalyst that can impose absolute stereochemical guidance at the stage of the [4+2] cycloaddition event.

We next turned to cases bearing C4 substitution on the dienophilic cyclenone substrate. As shown in Scheme 3, the facial stereoselection of the cycloaddition reaction is high (>10:1).25 At this writing, the ratio of Δ2:Δ 3 regioisomers in the double bond migration step in this series was somewhat disappointing.26,27 While the precise factors governing the selectivity of isomerization remain to be determined, they may well reflect minimization of peri interactions between C4 and C6 in the isomerized structure. Fortunately, we were able to retrieve the un-rearranged material and re-subject it to isomerization, thus improving our material throughput. Saegusa-Ito oxidation14,15 proceeded well to afford 17a and 18, respectively. That epimerization had not occurred at C6 during this step, was shown in the case of 17a by its non-identity with compound 17b, previously described and assigned in a rigorous way by Grieco and co-workers.28,29 Subjection of compound 17a to equilibrating conditions did, indeed, lead to epimerization, with emergence of 17b. Thus, the chemistry described above does lead to the otherwise difficultly accessible 6-axially alkylated Δ4 3-octalones.

This chemistry was next extended to a situation where the substituent on the cyclohexenone dienophile appears at C5. Four cases were examined (Table 1). As seen, the cycloadditions were, again, highly stereoselective, providing substantially one isomer in the Diels-Alder reaction.25 Again, silica gel mediation of the double bond isomerization occurred quite smoothly, this time in higher ratios than those contained in the 4-substituted series. Once again, Saegusa-Ito oxidations14,15 delivered the target octalones, this time bearing a substituent at C7,26
cis to the junction methyl group. This type of series is not readily generated from classical Robinson annulation strategies.

Adding to the patterns accessible by this logic was the fact that the chemistry is also extendable to the situation where the Diels-Alder diene contains a methyl substituent group at a terminal carbon30 (Table 2). Once again, the levels of face selectivity in the cycloadditions were excellent, giving rise to the major adducts shown. Silica gel mediated isomerizations afforded the "iso-DA-type" products in high ratios relative to starting DA adducts. Following Saegusa oxidation, there were obtained the octalones 33, 35, and 37 with a cis relationship between the junction (C10) and the C6 or C7 substituents.26 As discussed above, this stereopattern is not readily obtained from Robinson annulation strategies, either due to epimerization, in the case of the 6-substituted product, or because of the stereoelectronics of alkylation which govern the case where the substituent is at C7.

The applicability of this permuting of RA:DA logic was demonstrated in the context of two total synthesis programs. As will be seen, the targets were selected to exemplify the enhanced possibilities enabled by the chemistry described above. It was for the purpose of synthesizing the sesquiterpene carissone that we conducted the Diels-Alder reaction of 38 with 19.19,31 As shown in Table 2, cycloadition of 38 and 19 gave rise to a cycloadduct which underwent silica induced double bond isomerization, followed by Saegusa oxidation14 to afford 35. Not surprisingly,32 selective reduction of the non-conjugated ketone (C9) could readily be achieved to afford an alcohol (39), which, upon Barton deoxygenation,33 gave rise to 40. Deprotection, as shown, afforded (+)-carissone (41). We note that an elegant total synthesis of (+)-carissone, that does not draw from the chiral pool, has recently been described by Stoltz and colleagues.34 In the Stoltz synthesis, the C7–C10 stereorelationship was also managed through a non-RA program.

Recently, we noted a disclosure in the literature describing the isolation of a compound called cosmosoic acid (42)20 from Cosmos sulphureus, a plant native to Brazil and Mexico. This plant had been identified as a source of anti-malarial natural products, although antimalarial properties of 42, per se, were not reported. The gross structure and stereochemistry of cosmosoic acid had been determined strictly by spectroscopic methods, not supported by any degradative or crystallographic investigations.20 Given the Pattern Recognition Analysis line of thinking,16 one immediately notes the "iso-Diels-Alder" characteristic of cosmosoic acid.35 In this context, C3 of the C3–C4 iso-DA pattern carries a carboxyl group. One might well have considered synthesizing cosmosoic acid by a Diels-Alder reaction of diene 4336 with the generic dienophile 44, followed by isomerization of 45. To us, it seemed that such a program presented unlikely prospects for success. First, dienes of the type 43 tend to be quite unstable.37 Furthermore, the electron withdrawing carboxyl group at C2 would render this diene even less reactive in a hypothesized DA cycloaddition4-6 with an electron withdrawing dienophile of the type 44. Moreover, the key silica gel–mediated isomerization reaction has not been demonstrated in the context of octalin-related DA adducts arising from cycloadducts of the type 45. Instead, we preferred to resort to our usual 2-siloxybutadiene DA building block. If cycloaddition and isomerization would occur with appropriate selectivities, success would depend on converting the subsequently tautomerized ene-siloxy function in 47 to the corresponding unsaturated acid.

In the event, reaction of siloxydiene 4638 with the enone 4439 occurred quite smoothly in the presence EtAlCl2 to provide 49 in 90% yield. Happily, the silica gel–mediated isomerization of 49 proceeded, providing the isomerized silylenol ether (see 47). It seemed prudent to protect the ketone in the light of subsequent operations which were planned (vide infra). Remarkably, it was possible to convert the ketone function of 47 to its corresponding enol ether derivative, 50, via deprotonation with LDA and O-methylation with dimethyl sulfate. This method is not a common one for generating methyl enol ethers from ketones and could warrant future research as to its scope.

With compound 50 in hand, we turned to the conversion of the silylenol ether to the corresponding vinyl triflate. In the event, this subgoal was accomplished by generating the corresponding site-specific enolate via the action of 50 with methyllithium,40 whereupon quenching with the Comins reagent41 afforded the corresponding vinyl triflate 51. With compound 51 in hand, we examined the possibility of a modified Heck-carbonylation.42 Happily, this subgoal was accomplished relatively smoothly (75% yield) under the conditions shown. The intermediate acid was converted to its methyl ester 52. Hydrolysis of the enol ether function gave rise to ketone 53 in an overall yield of 75%. Saponification of the methyl ester gave rise to a product, tentatively assigned as structure 42.

Surprisingly, the NMR spectrum of presumed 42, thus obtained, exhibited certain clear differences from the NMR spectrum reported for cosmosoic acid.43 Obviously, we had reason to be concerned about a possible structural mis-assignment on our part, somewhere during our synthetic work. Upon reexamination of the intermediates generated in the total synthesis progression and our assignments along the way, we remained convinced that we had in fact synthesized 42 as shown. Happily, the matter was objectively established by an X-ray crystal structure of the synthetic material, which clearly revealed the end product of our total synthesis to be compound 42.44 At this stage, it seemed very likely that the structure of the natural product cosmosoic acid does not correspond to that shown in 42. Several attempts were made to network with the original authors,20 but these efforts did not provide any additional insight. No helpful samples or spectral readouts were obtained.

At the time of writing, we can only conclude that the structure of cosmosoic acid does not correspond to 42. Having no access to the natural product, itself, we are unable to provide an informed opinion as to the correct structure of naturally occurring cosmosoic acid.

Finally, we examined substitutions at C6 of the cyclohexenone (which would correspond to C8 of the resulting octalone26). In this connection we studied the case of compound 54.45 Attempted cycloadditions of 54 with diene 46 resulted in approximately 1:1 mixtures.46 Thus, the stereoguidance that we had successfully encountered in the cases of the 4- and 5-substituted 2-methylcyclohexenones, apparently does not provide useful margins with the 6-substituted system (cf. 54).25 This, in itself, is perhaps not surprising in the light of the nature of the Diels-Alder reaction.4-6 In the cycloaddition of a compound such as 54, one envisions the initial orienting bonding would occur at C3 of the cyclohexenone, and slightly later at C2 in the imperfectly concerted cycloaddition. That being the case, the methyl group at C6 would be only weakly directing, since it is in a 1,4-relationship to the emerging "lead" bond.

Conclusion

In summary, we have demonstrated modalities for permuting the stereochemistry and gross structural patterns emerging from a classical Robinson annulation (RA), with Diels-Alder (DA)-based technologies. The line of reasoning has led to stereospecific syntheses of carissone and the previously assigned structure of cosmosoic acid. In the latter case, the total synthesis work suggests that the structural assignment of the natural product is in error. We are hopeful that the successful demonstrations provided above for broadening the accessible relationships applicable to PRA can be applied to interchanging the structural and stereomotifs of other reaction dualities.

Answer: Controlled isomerization of the double bond of certain Diels-Alder reactions provides substrates that, upon oxidation, give rise to products whose gross structure corresponds to that of a Robinson annulation. In these cases, the stereochemistry of the Robinson annulation product reflects the fact that the initial combination occurred in a Diels-Alder mode. Using these principles, we have synthesized carissone and cosmosoic acid. In the latter case, our total synthesis raised serious questions as to the accuracy of the assigned structure of the natural product.


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:
briefly , poly(-caprolactone ) ( pcl ) were dissolved at 143 mg / ml in equal parts tetrahydrofuran and n , n - dimethylformamide , then extruded at 2.5 ml / h through a spinneret charged to + 13 kv .
the resulting nanofibrous jet was collected on a grounded mandrel rotating at 10 m / s and located 20 cm from the spinneret .
aluminum shields on either side of the spinneret were charged to + 9 kv to focus the jet . the spinneret was fanned back and forth to ensure uniform fiber deposition .
mscs were isolated from femoral and tibial bone marrow of 3 - 6 month old calves and expanded to passage 2 as described previously .
scaffolds were hydrated by sequential washes in 100 % , 70 % , 50 % and 30% ethanol and finally phosphate buffered saline ( pbs ) . before seeding ,
50 l of cell solution ( 1  10 cells / ml ) were applied to one side , followed by incubation at 37c for one hour .
scaffolds were then turned and an additional 50 l of cell solution applied to the other side .
after two hours further incubation , samples were transferred to chemically defined media ( dmem , 0.1m dexamethasone , 40 g / ml lproline , 100 g / ml sodium pyruvate , 1% insulin , transferrin , selenium / premix , and 1% penicillin , streptomycin and fungizone supplemented with 10 ng / ml transforming growth factor 3 ) . media was replaced twice weekly for the duration of the study . after measuring cross - sectional area using a custom laser device , samples ( n=5 ) were clamped with serrated grips and loaded into an instron 5542 testing device .
all testing was performed in a pbs bath . the mechanical testing protocol consisted of : ( 1 ) a nominal tare load of 0.1n applied at 0.1% strain / sec , followed by stress relaxation for 5 minutes , ( 2 ) 15 preconditioning cycles to 0.1% strain at 0.05% strain / sec , and ( 3 ) a quasi - static elongation at 0.1% strain / sec until failure .
strain was determined as extension normalized to gauge length ; stress was computed as the load normalized to initial cross - sectional area .
modulus was computed as the slope of the stress - strain plot , determined by regression to the linear portion of the curve . for biochemical analyses ,
samples were digested for 16 hours in papain at 60c , then analyzed for s - gag content using the 1,9-dimethylmethylene blue dye - binding assay , for orthohydroxyproline ( ohp ) content ( after acid hydrolysis ) to determine collagen content by reaction with chloramine t and dimethylaminobenzaldehyde , and for dna content using the picogreen dsdna quantification kit .
ohp content was converted to collagen with a ratio of 1 : 7.14 ( ohp : collagen ) .
paraformaldehyde - fixed sections were stained for cell nuclei ( 40,6-diamidino-2-phenylindole , dapi ) , glycoasaminoglycans ( alcian blue ) and collagen ( picrosirius red ) .
dapi - stained sections were visualized at 20 on a nikon t30 inverted fluorescent microscope .
quantitative polarized light microscopy was performed on picrosirius red stained sections to quantify collagen alignment as described previously .
briefly , grayscale images were collected ( 20 ) at 10 increments using a green bandpass filter ( bp 546 nm ) with crossed analyzer and polarizer coordinately rotated through 90. this was repeated with the filter replaced by a  compensator .
custom software was then used to determine collagen fiber orientations for a series of nodes within the central portion of each region of interest .
nanofibrous scaffolds of approximately 1 mm thickness were prepared as above and excised along the fiber direction .
two weeks of after seeding with mscs , samples ( n=5 ) were placed in apposition with a 20 mm overlap and secured with porous polypropylene and foil and cultured as above .
lap tests were performed by gripping the overhang on either end of the bilayer and extending to failure at 0.2 mm / s .
aligned nanofibrous scaffolds of approximately 1 mm thickness were excised at 30 from the fiber direction .
agarose was dissolved in pbs at 2 , 4 , 5 , and 6% w / v and melted by autoclaving .
molten agarose was applied between layers of scaffold , and allowed to set at room temperature .
no significant difference was observed in cross sectional area across all concentrations , indicating controlled , reproducible interface formation .
significance was established by p  0.05 as determined by two - way anova with a tukey 's post hoc test for independent variables of bilayer orientation ( parallel / opposing ) and culture duration ( or agarose concentration ) .
briefly , poly(-caprolactone ) ( pcl ) were dissolved at 143 mg / ml in equal parts tetrahydrofuran and n , n - dimethylformamide , then extruded at 2.5 ml / h through a spinneret charged to + 13 kv .
the resulting nanofibrous jet was collected on a grounded mandrel rotating at 10 m / s and located 20 cm from the spinneret .
aluminum shields on either side of the spinneret were charged to + 9 kv to focus the jet . the spinneret was fanned back and forth to ensure uniform fiber deposition .
mscs were isolated from femoral and tibial bone marrow of 3 - 6 month old calves and expanded to passage 2 as described previously .
scaffolds were hydrated by sequential washes in 100 % , 70 % , 50 % and 30% ethanol and finally phosphate buffered saline ( pbs ) . before seeding ,
50 l of cell solution ( 1  10 cells / ml ) were applied to one side , followed by incubation at 37c for one hour .
scaffolds were then turned and an additional 50 l of cell solution applied to the other side .
after two hours further incubation , samples were transferred to chemically defined media ( dmem , 0.1m dexamethasone , 40 g / ml lproline , 100 g / ml sodium pyruvate , 1% insulin , transferrin , selenium / premix , and 1% penicillin , streptomycin and fungizone supplemented with 10 ng / ml transforming growth factor 3 ) . media was replaced twice weekly for the duration of the study .
after measuring cross - sectional area using a custom laser device , samples ( n=5 ) were clamped with serrated grips and loaded into an instron 5542 testing device .
all testing was performed in a pbs bath . the mechanical testing protocol consisted of : ( 1 ) a nominal tare load of 0.1n applied at 0.1% strain / sec , followed by stress relaxation for 5 minutes , ( 2 ) 15 preconditioning cycles to 0.1% strain at 0.05% strain / sec , and ( 3 ) a quasi - static elongation at 0.1% strain / sec until failure .
strain was determined as extension normalized to gauge length ; stress was computed as the load normalized to initial cross - sectional area .
modulus was computed as the slope of the stress - strain plot , determined by regression to the linear portion of the curve . for biochemical analyses ,
samples were digested for 16 hours in papain at 60c , then analyzed for s - gag content using the 1,9-dimethylmethylene blue dye - binding assay , for orthohydroxyproline ( ohp ) content ( after acid hydrolysis ) to determine collagen content by reaction with chloramine t and dimethylaminobenzaldehyde , and for dna content using the picogreen dsdna quantification kit .
ohp content was converted to collagen with a ratio of 1 : 7.14 ( ohp : collagen ) .
paraformaldehyde - fixed sections were stained for cell nuclei ( 40,6-diamidino-2-phenylindole , dapi ) , glycoasaminoglycans ( alcian blue ) and collagen ( picrosirius red ) .
dapi - stained sections were visualized at 20 on a nikon t30 inverted fluorescent microscope .
quantitative polarized light microscopy was performed on picrosirius red stained sections to quantify collagen alignment as described previously .
briefly , grayscale images were collected ( 20 ) at 10 increments using a green bandpass filter ( bp 546 nm ) with crossed analyzer and polarizer coordinately rotated through 90. this was repeated with the filter replaced by a  compensator .
custom software was then used to determine collagen fiber orientations for a series of nodes within the central portion of each region of interest .
nanofibrous scaffolds of approximately 1 mm thickness were prepared as above and excised along the fiber direction .
two weeks of after seeding with mscs , samples ( n=5 ) were placed in apposition with a 20 mm overlap and secured with porous polypropylene and foil and cultured as above .
lap tests were performed by gripping the overhang on either end of the bilayer and extending to failure at 0.2 mm / s .
aligned nanofibrous scaffolds of approximately 1 mm thickness were excised at 30 from the fiber direction .
agarose was dissolved in pbs at 2 , 4 , 5 , and 6% w / v and melted by autoclaving .
molten agarose was applied between layers of scaffold , and allowed to set at room temperature .
no significant difference was observed in cross sectional area across all concentrations , indicating controlled , reproducible interface formation .
significance was established by p  0.05 as determined by two - way anova with a tukey 's post hoc test for independent variables of bilayer orientation ( parallel / opposing ) and culture duration ( or agarose concentration ) .

Answer:
successful engineering of load - bearing tissues requires recapitulation of their complex mechanical functions . given the intimate relationship between function and form , biomimetic materials that replicate anatomic form are of great interest for tissue engineering applications .
 however , for complex tissues such as the annulus fibrosus , scaffolds have failed to capture their multi - scale structural hierarchy .
 consequently , engineered tissues have yet to reach functional equivalence with their native counterparts . here
 we present a novel strategy for annulus fibrosus tissue engineering that replicates this hierarchy with anisotropic nanofibrous laminates seeded with mesenchymal stem cells .
 these scaffolds directed the deposition of organized , collagen - rich extracellular matrix that mimicked the angle - ply , multi - lamellar architecture and achieved mechanical parity with native tissue after 10 weeks of in vitro culture .
 further , we identified a novel role for inter - lamellar shearing in reinforcing the tensile response of biologic laminates , a mechanism that has not previously been considered for these tissues .


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:
pulmonary artery aneurysms and pseudoaneurysms are uncommon ; most are caused by infections , like tuberculosis , vasculitis ( behet 's syndrome ) or trauma , often iatrogenic ; less common causes include pulmonary hypertension , congenital heart disease , lung carcinoma , and connective tissue disease ( 1 - 3 ) . because of potential risk of high mortality , secondary to pseudoaneurysm enlargement and rupture , prompt
we , hereby , describe a case of ascending branch of the left pulmonary artery pseudoaneurysm , following a left upper lobectomy , for which a transcatheter endovascular embolisation of the aneurysm with intra - aneurysmal n - butyl 2-cyanoacrylate ( glue ) injection was performed .
a 30-year - lady had been presented to us 3 months ago with multiple episodes of hemoptysis and one major episode of 400 cc , and gave us a history of intermittent fever , cough , breathlessness and chest pain for a period of 2 - 3 months .
she was a known case of pulmonary tuberculosis with left upper lobe fungal ball ( pulmonary aspergillosis ) for the past 7 years .
she had had complete a course of anti - tuberculosis therapy and was asymptomatic until this period when she was presented to us with hemoptysis . at this time
the patient visited an emergency department again a month ago for exacerbation of the above symptoms .
because of the recurrent symptoms and deteriorating pulmonary function test results , the left upper lobectomy for pulmonary aspergilloma was performed .
the inferior pulmonary ligament was excised in order to enable the lower lobe to occupy the entire left thoracic cavity .
the early postoperative period was uneventful . in the third post - operative week , she started having streaky hemoptysis .
fibre optic bronchoscopy detected a normal tracheobronchial tree , however , the left upper lobe surgical closure site was congested and inflamed .
though the white blood cell count was normal , the patient was treated for a presumed chest infection .
the patient had spotty hemoptysis for the next two weeks , until she developed 2 - 3 episodes of massive hemoptysis of about 400 - 500 cc of blood .
patient was intubated and emergency computed tomography ( ct ) pulmonary angiography was done , which revealed a large pseudoaneurysm of the ascending branch of the left pulmonary artery ( fig .
because of the patient 's severe pulmonary insufficiency , she was not a surgical candidate and was referred to us for endovascular embolisation . under local anesthesia , with anesthetists standing by for emergency resuscitation if need arise , pulmonary angiography with 5 fr , 110-cm pigtail catheter ( cordis , johnson & johnson , new jersey ) was introduced via the right femoral venous approach , which showed approximately 3.5 cm aneurysm arising from the ascending branch of the left pulmonary artery , shortly after its origin ( fig .
then , a 5 fr , 100-cm head hunter catheter ( cordis , johnson & johnson , new jersey ) was introduced into the feeding artery of the aneurysm , just short of the aneurysm sac .
initially , we tried to occlude the feeding vessel with 35 - 5 - 5 and 35 - 8 - 8 coils ( cook , bloomington , in , usa ) , but both of these coils got misplaced proximally in the lateral basal and lower lobe trunk arteries , respectively .
because of larger diameter of the coils than the caliber of these arteries , the misplaced coils got stuck in a proximal part of the arteries . on an angiogram , we could see the uninterrupted rapid blood flow through the coils to the lower branches .
further , with digital road mapping , 5 fr head hunter catheter in the feeding artery , and acting as a guiding catheter , the aneurysm sac was catheterized with a 2.7 fr microcatheter ( terumo progreat ; terumo deutschland gmbh , germary ) .
now we decided to occlude the aneurismal sac by completely filling the sac with n - butyl 2-cyanoacrylate ( glue ) injection .
we calculated the volume of the glue mixture required in order to fill the aneurysm cavity by slowly calculating the volume of contrast injected , without causing the reflux of the contrast into the normal pulmonary circulation proximally .
the volume required was approximately 4 cc . to prevent a reflux , 5 cc of higher concentration i.e. 75% glue mixture of histoacryl ( braun , melsungen , germany ) and iodized oil ( lipiodol , andre guerbert , aulnay sous bois , france ) was taken in a 5-ml luer - lock syringe
, however we could only inject approximately 1.5 cc of the glue , as the microcatheter got blocked .
catheter sticking or breakage did not occur during the process of catheter retrieval and was immediately flushed vigorously with 5% dextrose to reopen the lumen .
check angiogram showed the glue cast in the central part of the aneurysm sac with aneurysm still filling in the periphery ( fig .
we now attempted to occlude the feeding artery with coil , but this time , the coil got dislodged in the aneurysmal sac .
now , the angiographic picture was much clearer , and on correlating with ct saggital reconstructed images , we got to know that the length of the feeding artery to the pulmonary artery aneurysm ( pap ) sac was very short .
so now , not to compromise the pulmonary circulation , we did not have any other option except to fill the sac either with coils or liquid materials .
in order to be economical on the cost , as well as our past experience with the glue , we decided to occlude pap with intra - aneurysmal injection of the glue .
we introduced the previously used microcatheter into the sac , and this time , we used 50% glue mixture and were able to fill the sac completely with calculated volume of 3 cc of liquid mixture without spillage into the proximal normal circulation .
post embolisation check angiogram showed a complete obliteration of the aneurysm sac with anterior ascending branch , and other branches of the left pulmonary artery being patent ( fig .
there was no alteration in the blood flow through the coils into the lower lobe branches , and therefore , we did not try to retrieve the coils .
ct performed on the 6th day showed glue cast with no filling of the aneurysm .
however , after being asymptomatic for 2 months , she presented again to our hospital with a single episode of 300 cc of hemoptysis .
emergency ct was performed , which did not show the new aneurysm or refilling of the previously embolised aneurysm ( fig .
1 g ) ; however , at this time , we could see a new aspergilloma in lateral basal segment of the lower lobe , and rib osteomyelitis ( fig .
at present , she is still admitted and is on a conservative management and being further investigated for these new ct findings .
pulmonary artery aneurysms and pseudoaneurysms ( paps ) are rare ; most are caused by infections , like tuberculosis , vasculitis ( behet 's syndrome ) or trauma , often iatrogenic , especially after swan ganz catheter insertion ; and less common causes include pulmonary hypertension , congenital heart disease , lung carcinoma , and connective tissue disease ( 1 - 3 ) .
thus , any destructive process of the lung , whatever its pathogenesis , can erode the vessels in its vicinity , be it a pulmonary or systemic vessel .
the etiology in this case can be attributed to inadvertent insult to the pulmonary artery during surgery for pulmonary aspergilloma .
also , after lobectomy , significant increase in the pulmonary vascular resistance index has been described in the literature ( 4 ) , and this could have had a possible contributory role for the development of the pseudoaneurysm .
another cause could be a low grade infection of the already weakened upper lobe pulmonary arterial wall , though the blood investigations were normal in our patient .
the most common cause for intrapulmonary bleedings is the hemoptysis , due to bronchial artery erosion seen in as many as 95% of all cases . in contrast , bleeding from the pulmonary arteries is very rare , usually massive , accounting for less than 5% of all cases ( 5 ) , and is usually due to pseudoaneurysm rupture . because of the risk of pap enlargement and rupture , which leads to death in approximately 50% of patients , prompt therapy is required .
the available treatment modalities for pap are medical therapy , surgery and percutaneous catheter embolisation of the pseudoaneurysm .
medical treatment by the means of immunosuppressive drugs and steroids has been found to cure or decrease the size of aneurysms in behcets disease ( 6 , 7 ) .
several surgical techniques , such as lobectomy , pneumonectomy , hilar clamping with direct arterial repair and ligation , have been used . however ,
in our case , due to the patient 's severe pulmonary insufficiency , she was not a surgical candidate .
there are number of reports in the literature addressing the treatment of paps - most of them using metallic coils ( 8) or silicon balloon ( 9 ) to occlude the arterial feeders .
these placements can also occlude the perfusion to aerated lung , distal to the embolisation site , and are associated with complications , like coil migration and damage to vessel wall .
other authors have occluded the pap by intraneurysmal placement of coils ( 10 ) ; however it carries a potential risk of mass effect and aneurysm rupture .
still , other authors have described the use of covered stents ( 11 ) , and recently , hovis and zeni ( 12 ) have used thrombin percutaneously for the paa refractory to coil the embolisation . in our case , initially , we attempted unsuccessfully to occlude the feeding artery with the coils .
however , the coils migrated proximally to enter into the lower lobe circulation without compromising the blood circulation to these segments .
we later realized that this was due to a short length and wide neck of the feeding artery , that we were not able to keep the catheter stable in this branch .
we did not want to occlude the aneurysmal sac with coils , firstly because of the large size of the lesion , use of multiple coils could result in a mass effect after embolisation , and secondly it would have been very expensive ; also it might be further complicated by coil migration , resulting from the wide neck of the aneurysm . in our case , because of regular and comfortable experience at tackling abdominal visceral aneurysms with glue embolization , we decided to use this liquid material as embolic material .
( 7 ) embolised the feeding branch to paa , using the glue with a " bubble technique " ; however , this was not possible in our case because of the short length in the feeding artery .
therefore , we considered the alternative option of intraaneurysmal injection of liquid embolic ( glue ) .
glue ( n - butyl 2-cyanoacrylate ) is a rapidly hardening liquid adhesive , and has been used as an effective embolic agent for brain vascular malformations ; however , necessity of operator experience with the use of liquid embolic material is a major limitation in its application to aneurysms .
there are some studies showing the feasibility of intraaneurysmal injection of the glue in intracranial aneurysms ( 13 ) , thereby keeping the antegrade flow in the aneurysm bearing artery patent .
we report the first case , in which the n - butyl 2-cyanoacrylate was successfully injected , intraaneurysmally , through the transcatheter route for the occlusion of a pulmonary artery pseudoaneurysm , after an upper lobe lobectomy for aspergillosis .
glue offers the advantage of permanent occlusion of the vessel , and because of its low viscosity , it can be injected through a microcatheter into small and tortuous arteries .
it is admixed with ethiodized oil in various ratios to achieve radiopacity and to adjust the polymerization time allowing for more controlled embolisation . the use of higher concentrations of glue results in quicker solidification ; however , on the contrary , the longer the polymerization time , the greater the risk of non - target embolisation because there is the possibility of embolic material being washed away before it solidifies . in our case
we initially used 75% glue to prevent the reflux into the parent artery ; however there was early polymerisation of the glue with the sac preventing an evenly distribution .
therefore , we had to dilute the glue to make it 50% concentration , and this time , there was complete filling of the aneurysm . in conclusion
intraaneurysmal injection of the liquid embolic materials is feasible , safe , and effective trancatheter treatment option for pulmonary artery aneurysms and is possibly not associated with the risk of rupture seen with packing of aneurysms with coils .
however , appropriate concentration of the glue , long term results , and etc . will require further experience to confirm its safety and efficacy in pulmonary circulation .

Answer:
we report a case of pseudoaneurysm of the anterior ascending branch of the left pulmonary artery , following a left upper lobectomy for pulmonary aspergillosis , for which we have done an endovascular treatment .
 this is the first case where complete pseudoaneurysm occlusion was accomplished after a transcatheter intra - aneurysmal n - butyl 2-cyanoacrylate ( glue ) injection .


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 global prevalence of diabetes mellitus has been remarkably increased during the last two decades and has reached from almost 30 million cases in 1985 to 285 million cases in 2010 ( 1 ) .
the prevalence of diabetes in iran was about 7.7% in 2005 ( 2 ) , and this amount reached 8.7% in 2007 ( 2 ) .
obviously , many factors are required to meet the needs of the patients with diabetes .
although , complete treatment of diabetes is a long way ahead , medical care and sociopsychological support have great effects on its acute and chronic outcomes ( 3 ) . in light of high prevalence of this disease , it has become the subject of significant research in different clinical areas . because of the increased prevalence of diabetes and its complex etiology ,
adaptation mechanisms are needed to make a change in the concepts of diabetes management and the treatment programs that have been considered so far .
this change should be from the physical variables to sociopsychological factors which may be effective on the disease management and its outcomes ( 4 ) .
in addition , the new treatment recommendations have specifically confirmed the importance of the integration of sociopsychological concepts with the usual care of patients with diabetes .
this new approach helps them achieve suitable control over their glucose level and leads to the person 's high compatibility ( 5 ) .
marital satisfaction is a situation in which husband and wife have a sense of happiness and are satisfied from each other most of the times .
satisfactory relationships between couples can be measured by mutual love , the amount of caring from each other , and understanding of each other ( 6 ) . according to winch ( as cited in olia ) , marital satisfaction is the adaptation between the individual 's present situation in marital relationships and his or her expected situation .
marital satisfaction does not appear from thin air and its development needs the effort of the couple .
the study results show that the outcome of marital satisfaction ( supporting each other ) can affect people s health ( 7 ) .
furthermore , a positive correlation has been found between marital conflict , anxiety , depression , and the low level of physical health ( 8) .
literature review in iran and other countries revealed that there has been no study about the relationship between marital satisfaction and compatibility with diabetes in patients with type 2 diabetes . despite benefiting from multiple therapeutic interventions like diets , regular exercise , weight control , chemotherapies , and epidemiologic investigations
the aim of the present study was to investigate the relationship between marital satisfactions with compatibility with type 2 diabetes .
this study method was descriptive - correlative . the sample consisted of patients ( 20 - 60 years old ) with diabetes who refereed to diabetes clinic in meybod , iran .
the patients with the following criteria were enrolled in the study : being 20 to 60 years old , having diagnosed their disease at least one year before the study , visiting one of the physicians in the diabetes clinic , and having medical case with the physician .
the people who had the following exclusion criteria were omitted from the study : having history of other physical diseases except the ones related to diabetes symptoms , and having mental retardation or other psychological disorders before diabetes diagnosis . according to the mentioned criteria , 160 patients from the clinic members ( 103 females and 57 males ) were randomly selected .
the sample size was determined based on random sample size formula of krejcie ( 9 ) which estimated to be 160 out of community of 280 patients . at first the list of the names of all people who were at that age range
they were called and those who had the criteria for entering into the study were chosen and invited for participating in the study . the questionnaires that were used in this study
they believed that this scale is related to the changes that happen during the individual 's life ( 10 ) .
this questionnaire included 47 questions rated in a 5-point scale from  completely agree  to  completely disagree .
the validity of the instruments was also calculated by content validity method and its reliability was calculated by retest method ( 0.82 ) that was significant ( 11 ) .
the factors are family relationships , relationship with friends , dependency and independency conflicts , physical image , and the attitude toward the disease .
these factors show how diabetes affects the individual 's way of living and his or her compatibility .
those responses that show positive compatibility with diabetes were given the score of 1 and those which show negative compatibility were given 0 .
the reliability of this questionnaire with retest method on 15 patients with diabetes was found 0.73 after 5 weeks , and its content validity was confirmed by 3 psychologists and endocrinologists and psychiatric nursing .
they believed that this scale is related to the changes that happen during the individual 's life ( 10 ) .
this questionnaire included 47 questions rated in a 5-point scale from  completely agree  to  completely disagree .
the validity of the instruments was also calculated by content validity method and its reliability was calculated by retest method ( 0.82 ) that was significant ( 11 ) .
the factors are family relationships , relationship with friends , dependency and independency conflicts , physical image , and the attitude toward the disease .
these factors show how diabetes affects the individual 's way of living and his or her compatibility .
those responses that show positive compatibility with diabetes were given the score of 1 and those which show negative compatibility were given 0 .
the reliability of this questionnaire with retest method on 15 patients with diabetes was found 0.73 after 5 weeks , and its content validity was confirmed by 3 psychologists and endocrinologists and psychiatric nursing .
most of the study samples were in the age range of 41 - 50 with the frequency of 50 which involves 31.2% of the participants and the least frequency was in the age range of 21 - 30 with 11 ( 6.8% ) participants . also , most of the participants were women 103 ( 64.4% ) .
table 1 shows the mean and standard deviation of marital satisfaction and the aspects of compatibility with diabetes in the sample group .
table 1 shows that the mean and standard deviation of marital satisfaction in the sample group are respectively 136.9 and 14.07 , and the mean and standard deviation of compatibility with diabetes are respectively 40.12 and 3.33 .
table 2 shows the result of anova ( analysis of variance ) on the mean of marital satisfaction score in two groups ( men and women with diabetes ) .
table 2 shows that , there is no significant difference between women and men with diabetes regarding marital satisfaction ( p = 0.3 ) .
table 3 shows the correlation between marital satisfaction and aspects of compatibility with diabetes in women and men with diabetes .
table 3 shows that a positive , significant relationship exists between marital satisfaction and compatibility with diabetes in women ( p = 0.006 ; r = 0.26 ) .
it means that as marital satisfaction increases in women with diabetes , compatibility with diabetes will also increase .
however , there is no significant relationship between marital satisfaction and compatibility with diabetes in men with diabetes ( p = 0.87 ; r = 0.02 ) .
also , there is no significant relationship between aspects of compatibility with diabetes and marital satisfaction in women and men .
as it was mentioned , the present study was carried out to investigate the relationship between marital satisfaction and compatibility with diabetes in patients with type 2 diabetes .
the results revealed that a positive significant relationship exists between marital satisfaction and compatibility with diabetes in women .
it means that by increasing marital satisfaction , compatibility with diabetes increases and vice versa .
in fact , marital satisfaction affects people 's mental health and these result are in consistent with the results of other studies ( 12 , 13 ) in which the relationship between mental health and marital satisfaction were investigated in people with chronic diseases .
the results of the other studies ( 14 , 15 ) in which the relationship between family support and blood glucose control was investigated in elderly with type 2 diabetes revealed that family support increases marital satisfaction which is in line with increasing the elderly mental health .
elder and george ( 16 ) also cited in their study that close relationships are the main source of pleasure and support during life .
people who have closer relationships are in better physical and mental health condition ( 16 , 17 ) which is consistent with the results of this study .
lal and bartle - haring ( 18 ) investigated marital satisfaction in patients with chronic lung diseases and their results also revealed that marital satisfaction was related to psychological improvement which could affect and alleviate their chronic pains .
whitsitt ( 19 ) investigated coping strategies and compatibility with coronary artery diseases in couples and the results showed that marital quality can affect better compatibility with the disease .
20 ) revealed in their studies that the relationship between the couples can reinforce the behaviors related to health and lead to people 's improvement .
therefore , this issue destroys the balance of suitable behaviors and leads to loss of intimacy .
marital satisfaction is considered as a continuum and an evolutionary process between husband and wife .
marital satisfaction includes some elements such as self - esteem , self - effectiveness , domination , and control over life .
the weakness in any of these factors leads to the reduction in individual 's health and ability for dealing with his or her present conditions .
in fact , marital satisfaction acts as a protective and reinforcing factor for the patient .
when marital satisfaction is high , domination , control , and life expectancy will increase in the person and he or she tries more to improve himself or herself .
when marital satisfaction is high , the person also benefits from the advantages of this relationship which occurs in a substitutive way and he or she can adopt his or her condition . in this study the interaction of variables like occupation , education , duration of marriage , number of children , personality , place of living , and other effective social and cultural variables were not examined with the test variables .
therefore , it is suggested that the relationship of test variables with other variables such as age , gender , education , duration of marriage , and personality be investigated in different cities .
in addition , this study has its own limitations like the small number of the subjects who were a group of patients referred to the hospitals in meybod .
so , further studies should be done , in different cities and on other age groups with other instruments and the results should be compared . in the future studies it is important to consider other psychological factors too , since investigating possible interactive effects of some personal issues in predicting compatibility with type 2 diabetes can help us in explaining problems regarding diabetes management in a more suitable way .

Answer:
background : marriage is a legal pact between a man and a woman for participating in a social life together which can play an important role in dealing with difficulties.objectives:this study was carried out to investigate the relationship between marital satisfaction and compatibility with diabetes in patients with type 2 diabetes.patients and methods : the study method was descriptive - correctional .
 the study sample included 160 diabetic patients ( 103 females and 57 males ) who were randomly selected .
 the instruments used were enrich marital satisfaction questionnaire and the questionnaire of compatibility with diabetes .
 in addition , the data were analyzed through descriptive statistics and analysis of variance by spss.results:the result of the study revealed a significant correlation ( p = 0.006 ) between marital satisfaction and compatibility with diabetes in women with type 2 diabetes ( r = 0.26 ) .
 however , this correlation was not significant in men with diabetes . also , a significant relationship existed between the dimensions of compatibility with diabetes and marital satisfaction in both men and women with diabetes.conclusions:marital satisfaction affects compatibility with diabetes in women .
 therefore , it might be possible to increase compatibility with diabetes in them by offering specialized interventions as family and couples therapies and giving consultations .


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:
autoimmune polyglandular syndrome ( aps ) is a rare genetic disease that causes multiple endocrine disorders .
the vague presentation of endocrine dysfunction can cause a delay in both the diagnosis and the treatment of life - threatening conditions .
we , herein , present a case of aps in a 21-year - old man whose condition did not respond to initial treatment and in whom a definitive diagnosis was subsequently achieved by workup for hypocortisolism .
a 21-year - old man with a history of hashimoto 's thyroiditis with hypothyroidism presented to the emergency department for evaluation of an altered mental status .
he was very lethargic , stared blankly , and was unable to respond appropriately to questions .
he reported no fever , difficulty swallowing , shortness of breath , muscle or joint pain , headache , vomiting , or excessive thirst or urination .
physical examination revealed a temperature ( t ) 34.3c , heart rate ( hr ) 68/min , respiratory rate ( rr ) 16/min , and blood pressure ( bp ) 87/57 mmhg .
he was very lethargic , confused , and able to answer only yes - or - no questions .
the patient exhibited hyponatremia ( 128 meq / l ) , hypoglycemia ( 29 mg / dl ) , and a high thyroid - stimulating hormone ( tsh ) level ( 14.31 iu / ml ) .
test for other metabolic panel , complete blood count , triiodothyronine and thyroxine levels , head computed tomography , and urine toxicology screening results were all normal .
he was diagnosed with severe hypothyroidism and received 2 l of fluid for resuscitation , 25 g of dextrose , and a single intravenous ( iv ) dose of 100 mcg levothyroxine at the emergency department .
a random serum cortisol level was < 1.0 g / dl . a 250 g adrenocorticotropic hormone ( atch ) stimulation test was < 0.1 g / dl . he was diagnosed with primary adrenal insufficiency and received a treatment with iv hydrocortisone .
his mental status , generalized fatigue , and metabolic parameters including glucose and sodium levels substantially improved .
aps type 2 ( aps2 ) was suspected based on his history of hypothyroidism and primary adrenal insufficiency .
the results of an additional liver function test , anti - gad65 antibody titer , testosterone level , and plasma renin activity were all within normal limits .
the patient had returned to his normal level of activity by the time of the outpatient follow - up and reported feeling much better after treatment with hydrocortisone , fludrocortisone , and levothyroxine .
the present case illustrates an example of aps2 , the clinical presentation of which may overlap that of primary adrenal insufficiency and hypothyroidism due to autoimmune thyroiditis .
the present patient exhibited lethargy , an altered mental status , hypothermia , hypotension , hypoglycemia , an elevated tsh level , and normal thyroxine levels .
he was later found to have primary adrenal insufficiency and his clinical symptoms improved after receiving corticosteroid replacement therapy .
other autoimmune diseases , especially of the skin , stomach , and gonads , may occur with increased frequency in patients with aps2 .
the greatest danger associated with aps2 is treatment of the presenting hypothyroid state without recognition of concomitant hypoadrenalism .
hypothyroidism reduces cortisol clearance , and the addition of thyroid hormone replacement increases cortisol clearance .
additionally , hypothyroidism reduces the metabolic rate , thereby , reducing the need for cortisol . the increased metabolic rate accompanying thyroxine replacement increases the requirement for cortisol .
furthermore , a high serum concentration of tsh in the absence of primary thyroid failure can be a feature of adrenal insufficiency .
the development of an adrenal crisis due to underlying adrenal insufficiency has been reported after the administration of thyroxine replacement therapy to patients initially thought to have only hypothyroidism .
the management of aps2 is based on individualized , lifelong replacement therapy for the affected endocrine organs plus monitoring for development of insufficiency in other organs or associated conditions .
the use of medical alert sensors and other measures should be taken to ensure that adrenal function is considered during illness , surgery , or emergency situations .
in summary , we have reported a case involving a patient with aps2 who presented with lethargy , hypotension , hypoglycemia , and an elevated tsh level .
the vague presentation of this syndrome can cause missed or delayed treatment for adrenal insufficiency resulting in a life - threatening adrenal crisis .

Answer:
context :
 autoimmune polyglandular syndrome is a rare condition that causes a variety of clinical symptoms due to autoimmune processes involving multiple endocrine organs . its vague presentation can cause missed or delayed treatment for adrenal insufficiency , resulting in a life - threatening adrenal crisis.case report : a 21-yr - old man presented with lethargy , hypotension , hyponatremia , hypoglycemia , and an elevated thyroid - stimulating hormone level .
 he was binge drinking the day before presentation .
 no significant response to initial treatment with levothyroxine and dextrose occurred .
 diagnostic workup later revealed primary adrenal insufficiency .
 all initial symptoms completely resolved following treatment with hydrocortisone , fludrocortisone , and levothyroxine.conclusion:autoimmune polyglandular syndrome causes dysfunction of multiple endocrine organs such as the thyroid gland , adrenal gland , and pancreas . initial diagnosis of aps is crucial and difficult because of its vague , acute presentation , which often involves hypothyroidism and adrenal insufficiency .
 delayed treatment of adrenal insufficiency can result in a life - threatening adrenal crisis . a diagnostic workup for adrenal insufficiency
 should be performed in patients who do not respond to hypothyroidism treatment .


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:
a study on serologic and molecular characterization of denv isolates was initiated in january 2005 at the fundao de medicina tropical do amazonas ( fmtam ) .
parasite - negative patients who had clinical symptoms of malaria were invited to participate in the study .
each patient received essential information and signed a consent form approved by the fmtam ethical committee .
all serum samples were collected during the acute phase of illness and tested for denv infection by using 3 methods .
the first method was virus culture , for which serum samples were placed on the aedes albopictus cell line c6/36 grown in leibovitz-15 medium containing 5% fetal bovine serum , followed by viral antigen identification with type - specific monoclonal antibodies in an indirect immunofluorescence assay ( 8) . the second method was detection of immunoglobulin m antibodies to denv by an elisa on serum samples from patients > 7 days after onset of symptoms ( 9 ) .
pcr ( rt - pcr ) protocol on the basis of that described by lanciotti et al .
briefly , viral rna was extracted by using the qiaamp viral rna mini kit ( qiagen , valencia , ca , usa ) , and reverse transcription was conducted on 5 l of extracted rna with superscript iii ( invitrogen , carlsbad , ca , usa ) and random primers .
after incubation for 1 h at 50c , 2 l of each cdna was subjected to pcr amplification with d1 and d2 primers for 35 cycles consisting of 1 min at 94c , 1 min at 55c , and 1 min at 72c , and a final extension for 10 min at 72c .
a second round of amplification was conducted with 10 l ( diluted 1:100 ) of the first amplicon , a mixture of type - specific reverse primers ( ts1ts4 ) , and the conserved forward primer d1 .
denv-4 was detected in 3 samples ( am750 , am1041 , and am1619 ) by virus culture or rt - pcr .
it was identified as a co - infecting virus with denv-3 in isolate am750 ; samples am1041 and am1619 represented single denv-4 infections ( table ) . to confirm these results ,
generated amplicons were cloned into a ta vector ( invitrogen ) , and > 3 colonies for each sample were sequenced in both directions by using the bigdye terminator cycle sequence kit ( applied biosystems , foster city , ca , usa ) .
denv-3 and denv-4 nucleotide sequences obtained were subjected to a basic local alignment search tool ( blast ) ( www.ncbi.nlm.nih.gov/ ) analysis that used the megablast algorithm optimized for highly similar sequences . using this approach , we obtained sequences with identities ranging from 95% to 99% for denv-3 and 94% to 98% for denv-4 for isolates am750-d3 , am750-d4 , and am1619 .
eu127898 ( am750-d3 ) , eu127899 ( am750-d4 ) , and eu127900 ( am1619 ) .
* igm , immunoglobulin m ; m - pcr , multiplex typing pcr described by lanciotti et al .
( 10 ) ; s - pcr , single serotype - specific primer pcr ; d , dengue serotype ; blast , basic local alignment search tool ; ns , not sequenced .
isolate am750 is from a person with a co - infection ; different clones were sequenced .
the 3 denv-4positive samples were obtained from patients who lived and worked in manaus and reported no travel history for > 15 days before onset of symptoms .
these samples were obtained during another study that identified 62 denv - positive samples from january 2005 through june 2007 ( 24 denv-2 , 35 denv-3 , and the 3 denv-4 cases in our study ) among 128 samples tested from patients in 14 municipalities in amazonas .
since its introduction into the western hemisphere in 1981 , denv-4 has been associated with dengue fever and only sporadically associated with serious cases of dhf or dss ( 1 ) .
a study in colombia found more dhf patients infected with denv-2 than with denv-3 or denv-4 ( 11 ) .
conversely , another study showed an association of denv-4 with an epidemic of dhf that occurred in mexico in 1984 ( 12 ) .
there are many host ( and perhaps viral ) factors in dengue infections that may lead to development of dhf . on the basis of the antibody - dependent enhancement hypothesis
, the most important factors would be those generated by the patient s immune response upon secondary infections ( 13 ) .
the 3 isolates reported in our study were from patients with no travel history , which indicates that denv-4 is present in manaus .
detection of denv-4 in brazil co - circulating with other denv serotypes endemic to this country represents an increased risk for dhf or dss because many persons have been sensitized by previous dengue infections but are not protected against infection with denv-4 .
the first report of denv-4 in brazil was in the state of roraima in 1982 .
since that time , no other isolate of denv-4 has been reported in any part of brazil ( 14,15 ) .
the resurgence of denv-4 in the amazon region of brazil most likely resulted from the proximity of brazil to denv-4endemic countries ( venezuela and colombia ) .
additional genotyping studies are being conducted to verify this assumption and to obtain information on dengue epidemiology in brazil .
our study documents the detection of denv-4 in manaus , amazonas , and the first isolation of this serotype in brazil in 25 years .
these findings reinforce the need for continual epidemiologic studies and use of classic and molecular approaches in the surveillance of emerging or reemerging diseases .

Answer:
we report dengue virus type 4 ( denv-4 ) in amazonas , brazil .
 this virus was isolated from serum samples of 3 patients treated at a tropical medicine reference center in manaus .
 all 3 cases were confirmed by serologic and molecular tests ; 1 patient was co - infected with denv-3 and denv-4 .