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:
congenital adrenal hyperplasia ( cah ) refers to a group of autosomal recessive disorders caused by an enzyme deficiency which leads to defects in biosynthesis of steroid precursors .
depending on the severity and degree of 21 hydroxylase deficiency , the clinical spectrum may vary from mild form of non classical cah to classic cah .
however , the non classical cah variant is more common with a prevalence rate of 1 in 1000 .
it also helps in maintaining normal levels of precursors by suppressing adreno cortico trophic hormone ( acth ) . during childhood
, the management is largely focused on achieving normal growth and attaining appropriate final adult height .
johns medical college hospital , bangalore by the department of endocrinology on patients diagnosed to have cah and seen in the outpatient clinic between january 2012 and october 2012 . during this period
data regarding demography , clinical presentation at time of diagnosis , treatment details , height sds and bmi were collected .
all patients underwent biochemical testing for 17 hydroxy progesterone ( 17 ohp ) levels for assessment of adequacy of therapy . bone age assessment with left hand and wrist
bmi was calculated for all patients and obesity was defined using who charts as values above 95th percentile .
17 ohp levels between 1 ng / ml and 12 ng / ml were considered appropriate ; values below 1 ng / ml suggested suppression and over treatment and values above 12 ng / ml suggested under treatment .
29 patients were included in the study of which 22 were females ( 76% ) and 7 were males ( 24% ) . based on the cross sectional data collected , 11 patients were adults ( age > 18 ) and 18 patients were children ( 62% ) . among the males ,
one child was identified at birth via a neonatal screening program , one child presented with early pubarche , the other 5 infants presented between their 3rd and 6th week of life with features suggestive of adrenal crisis - poor feeding , vomiting and failure to gain weight .
one of the male patients incidentally also had a penoscrotal hypospadias which was surgically corrected . among the females ,
9 infants were identified at birth due to presence of genital ambiguity ( 40% ) , 1 presented with symptoms of adrenal crisis at 4 weeks of life , 4 patients presented in the pre pubertal period due to early onset adrenarche ( 18% ) , 5 patients presented in the late adolescent period with marked virilization ( 23% ) and 3 patients presented with features of poly cystic ovarian disease ( pcos ) .
all the five patients who presented in the late adolescent period had obvious genital ambiguity from birth , however , they sought medical attention only much later due to marked virilization and failure to attain menarche .
one among them had actually been evaluated and even underwent a clitoroplasty at a young age , but unfortunately , the diagnosis of cah was missed as she was mistakenly categorized as probable ovo testicular dsd due to presence of mullerian structures with a phallic length of around 6 cm .
all these 5 women had a masculine built at presentation with poor breast development , severe hirsutism , muscular body habitus , temporal balding and varying degrees of deepening of voice .
the non classical cah ( nccah ) patients presented in adulthood with complaints of irregular cycles and hirsutism ; they had no features of virilisation .
simple virilizing was the most common sub class seen among the women ( 81% ) whereas the salt wasting type was predominant among boys ( 85% ) .
around 35% of patients had short stature as defined by height sds < -2.0 ; 2 patients who presented with adrenarche had increase in height sds , however , their bone age was also correspondingly advanced .
all the children were treated with hydrocortisone ; almost all adult patients were on dexamethasone .
none of the nccah patients were treated with glucocorticoids ; they were on anti - androgen therapy along with oral contraceptive pills .
most adult classic cah patients with complaints of hirsutism were treated with either spironolactone or finasteride .
pubertal induction with ethinyl estradiol was initiated for three of the adult patients who sought medical care late .
analysis of 17 ohp levels revealed that 32% were suppressed with levels less than 1ng / ml ; appropriate in 47% and inadequate in 21% of patients .
we report the phenotypic features of a cohort of patients with cah being evaluated and managed in a tertiary centre in southern india . in this series ,
the typical presentation of male babies were with adrenal crisis between the 3 and 6 week of life . around 20% of female patients with classic cah
were identified and appropriately treated only after late adolescence even when genital ambiguity was present since birth .
short stature was seen in one third of patients on therapy and the average final adult height among patients with classic cah was 142.37 , which was significantly lower than the mean adult height for females in our population .
the mean final adult height of 157.5 cm for those with nccah was better than their classic cah counterpart .
obesity and hypertension were not found to be significantly higher in this cohort of cah patients .
one third of patients had suppressed 17 ohp levels suggestive of over replacement therapy which may also contribute to the reduction in the final adult stature .

Answer:
congenital adrenal hyperplasia is a group of autosomal recessive disorders caused by enzyme deficiency which leads to defects in biosynthesis of steroid precursors .
 most common is 21 hydroxylase deficiency .
 clinical spectrum varies from non - classical cah to classic cah , and it may be simple virilising form or salt - wastinfg type .
 29 patients were included in our study from january 2012 to october 2012 .
 76% were females .
 male babies typically presented with adrenal crisis between 3rd to 6th week of life . around 20% of females
 were identified and appropriately treated only after late adolescence .
 short stature was seen in 1/3rd of patients .
 1/3rd of patients had suppressed 17 ohp levels suggestive of over - replacement therapy which may contribute to final reduction in adult height .


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:
improperly - placed implants are at risk of dislocation , increased component wear and loosening , and the need for revision surgery .
avoiding glenoid component malposition in terms of version and inclination is therefore an important technical goal , which may be very demanding due to a variety of issues related to patient anatomy and surgical technique .
altered anatomy in revision cases , joint contractures and complex patterns of glenoid bone loss with unreliable landmarks are commonly encountered in this patient population . in such cases , directing the glenoid baseplate along an appropriate axis with sufficient bone stock for fixation may be a challenging intra - operative task .
surgical planning for these patients can be improved using three - dimensional ( 3d ) reconstructions of ct scans , but recreating that same plan at surgery can be difficult .
computer navigation has been employed for this purpose , with promising results . however , computer - assisted glenoid implantation techniques use an intra - operative setup using a tracking system , with some disadvantages : instrumentation is cumbersome to use in the shoulder ; pins used for array fixation may cause iatrogenic lesions such as fracture or neurovascular injury ; registration of anatomical landmarks may be inaccurate ; and the need for resetting may result in an increase in operative time of more than 20%
patient - specific instrumentation has the potential to provide a similar level of accuracy as computer - assisted navigation , but without such problems or additional surgical steps .
this type of pre - operative planning has grown in popularity across a wide range of orthopaedic subspecialties including total hip and knee arthroplasty , pelvic and acetabular procedures and spinal deformities , with varying degrees of success .
it is the most recent development in this field , and its effectiveness in both the version and inclination planes of glenoid component placement has been demonstrated for both total anatomical and reverse shoulder arthroplasties .
patients undergo a pre - operative thin - cut ct scan of the entire scapula and adjacent humerus following a predefined protocol .
original two - dimensional ( 2d ) images are uploaded to a 3d image processing software system and reformatted into accurate 3d models of the scapula , in order to avoid errors in measuring actual version or inclination  the plane of image acquisition ( gantry angle ) can deviate from a perpendicular angle to the plane of the scapula .
this plane of the scapula is defined by three landmark anatomical points : the inferior scapular angle point , the glenoid centre point and the trigonum spinae point ( intersection of scapular spine and medial border ) .
a neutral inclination axis , or glenoid centre line , is defined between the last two ( fig .
1 ) . the version is therefore measured with respect to the scapular plane , and inclination with respect to the neutral axis , as the angle between a line perpendicular to it and a line from the superior to inferior rim of the glenoid .
three anatomical points ( red dots ) used as landmarks for the definition of the scapular plane and the neutral inclination axis ( red line ) : the inferior scapular angle point , the glenoid centre point and the trigonum spinae point .
the pre - operative planning is performed by the surgeon using adequate software , in a process that may vary according to each provider ( fig .
virtual surgical planning requires the definition of the axis for the glenoid baseplate component , by creating patient - specific surgical guides .
the guide is designed to fit onto the surface and border of the glenoid in each specific case , requiring minimal additional exposure , and is manufactured following a 3d stereolithography model .
this guide , constructed from a sterilisable material ( usually polyamide resin ) has one or two drill cylinders positioned to orientate the drilling of the central glenoid guide pin . in addition to this glenoid guide , a patient - specific glenoid vault replica is also created to aid the surgeon in having the best perception of the placement of the guide on the glenoid during surgery ( fig .
a ) radiograph and b ) mri of a shoulder with extensive glenoid destruction for a reverse prosthesis ; c ) coronal , and d ) transverse view of the pre - operative planning .
a ) sterilised bone model and glenoid guide , with b ) one inferior - tilted pin hole for a reverse procedure and a second superior one for an anatomical procedure .
the technique for exposure and the use of instruments for bone preparation over a guidewire is identical whether or not the patient - specific instrumentation is used .
the only additional requirements are care not to resect bony prominences such as osteophytes that were contemplated in the development of the guide and are necessary for the proper seating of the guide , and a slightly more extensive exposure of the anterosuperior aspect of the glenoid and base of the coracoid .
this fact , however , may make the use of the deltopectoral approach more favourable as it may facilitate glenoid exposure , which is in fact the only restriction the surgeon may find in using a superior transdeltoid approach .
the guide is then fitted to a stable position on the native glenoid and the central kirschner wire ( k - wire ) is drilled into the glenoid until the far cortex is perceived ( fig .
this k - wire then guides further cannulated glenoid reaming and subsequent steps for both total and reverse shoulder arthroplasties according to standard guidelines of the manufacturers ( fig .
a ) glenoid central pin placement for an anatomical prosthesis in a right shoulder ; b ) good exposure of the anterosuperior glenoid rim is required for the proper seating of the guide .
a ) reverse prosthesis in a left shoulder and guided central pin drilling ; b ) native glenoid and patient - specific bone models are compared to check accurate placement of the guide on a very deformed scapula ; c ) central screw drilling completed over a guide pin that keeps its stability due to the integrity of the far cortex with no glenoid vault perforation , made possible with an accurate drilling direction .
in addition to single - use patient - specific instrumentation ( psi ) , it should be noted that reusable and adjustable psis are also available from some manufacturers . in the longer term , this technology may prove to be of lower cost than single - use psis and should result in a reduction of the time from planning to use of the instrument .
in addition to single - use patient - specific instrumentation ( psi ) , it should be noted that reusable and adjustable psis are also available from some manufacturers . in the longer term , this technology may prove to be of lower cost than single - use psis and should result in a reduction of the time from planning to use of the instrument .
no long - term clinical studies comparing patient - specific to standard instrumentations have been published to date , and the few reports on this subject that have been published are mostly laboratory studies on cadaver specimens , evaluating the accuracy of the baseplate positioning .
the purpose of those studies was to examine the effectiveness of patient - specific planning and a patient - specific drill guide for glenoid component placement in shoulder arthroplasty .
the conclusions drawn are similar in all . in 2011 , suero et al evaluated the safety and accuracy of a custom glenoid jig created using pre - operative ct imaging , with 3d modeling for glenoid component implantation .
comparison between the pre - operative plan and the result on post - operative ct scans of seven patients showed that a ct - based custom alignment can reliably guide the placement of the glenoid component during conventional and reverse shoulder arthroplasty , without technical difficulties or complications . in their level
i randomised prospective clinical trial , hendel et al concluded that there was a significant improvement in the accuracy of glenoid component placement with the use of patient - specific guides in patients with bone deformity and glenoid retroversion in excess of 16 , and no difference in those with glenoid retroversion below 7. levy at al later concluded that the use of patient - specific guides in 14 reverse arthroplasties was highly accurate in reproducing a virtual 3d pre - operative plan , delivering the accuracy observed using computerised navigation without any additional surgical steps or technical difficulties .
likewise , walch et al demonstrated in an in vitro study that using 3d planning software and custom guides is a reliable and precise option in total shoulder arthroplasty . the most recent papers from 2015 further support those conclusions .
in 36 prostheses , heylen et al found that patient - specific guidance reduced variability in glenoid component inclination , as well as the risk of extreme inclination errors for total and reverse shoulder arthroplasty when compared with standard pre - operative planning and instrumentation . in a multi - surgeon study in 70 arthritic cadaver specimens ,
throckmorton et al found that these patient - specific targeting guides were significantly more accurate ( p = 0.01 ) for the combined vectors of version and inclination , and also had fewer instances of significant component malposition than traditional instrumentation .
3d surgical planning and patient - specific guidance reduce variability in glenoid component inclination , which should result in fewer malpositioned glenoids in both total and reverse shoulder arthroplasty . in severe glenoid deformations ,
namely when bone grafting is required , psi will aid in estimating the best alignment , in terms of version and inclination , as well as the best fixation on stable bone stock , avoiding glenoid vault perforation ( figs 6 and 7 ) .
good baseplate alignment on the same patient as shown in figs 2 and 5 , with severe glenoid deformation requiring bone grafting .
digitised image from pre - operative plan of an anatomical glenoid component , displaying peg penetration from the vault posteriorly .
( from zimmer - biomet software ; with permission ) . however , there are a few important points that need consideration when using this technology .
first , manufacturing the psi guide is based on an accurate 3d model of the patient s scapula made from ct - scan cuts , which may be conditioned by cartilage loss , severe bone deformity or calcified labrum .
second , seating the guide properly on the native glenoid demands good exposure of the anterosuperior glenoid rim , with removal of any soft tissues that may impair it .
third , reaming to the adequate depth and orientation is still dependent on the surgeon s ability , as bending or pushing the guide pin with the reamer can mislead further reaming . likewise , overtightening screws on soft bone or graft may asymmetrically overcompress the glenoid component against bone and change its final position , despite adequate reaming over a well - positioned central pin .
hendel reported four in 15 cases with over 10 of deviation in version or inclination from the pre - operative plan , despite the use of psi , all performed by surgeons with little experience with this technology . by way of addressing these limitations ,
some manufacturers have developed multiple psi guides to help correct off - axis reaming , control the depth of reaming and assist in the orientation of the fixation screws .
current evidence suggests that the use of psi can assist in the avoidance of significant glenoid baseplate orientation errors , especially by less experienced surgeons , resulting in fewer malpositioned glenoid components .
custom - made guides will play an important role in the placement of the central pin on glenoids with severe deformation , in cases where the best anatomical landmarks may have vanished and the use of bone grafting is anticipated .
however , the surgeon s expertise and intuition remains invaluable , both in the pre - operative planning and in the final component implantation , especially concerning the reaming depth .
however , psi seems to offer a distinct advantage to lower - volume surgeons , by reducing the risk of guide - pin malposition , a step that is very much dependent on the surgeon s expertise .
furthermore , pre - operative planning time is longer and may be dependent on external technical support , limiting its usage to elective surgeries and making it unsuitable for acute cases such as fractures .
psi offers a greater chance of accurate alignment of the glenoid component , which seems to be an advantage .
however , scapulae are not all the same , so when we try to align all glenoids in the same way , we may actually be changing the native alignment of some shoulders . predicting the physiological glenoid version for
a particular pathologic shoulder can be difficult , unless comparison with a normal contralateral shoulder ( if present ) is done .
scalise et al concluded that a 3d vault model , as described by codsi et al , could be used as a template to predict normal or baseline glenoid version for a particular patient .
youderian and iannotti have concluded from surgical simulation in a 3d virtual environment that additional use of a patient - specific glenoid vault can predict pre - morbid version , inclination and amount of volumetric bone loss , which can help to generate the best possible scenario of bony structural support for the glenoid implant and can minimise the amount of bone loss , by reaming .
these findings are invaluable for further development of systems which may help surgeons in estimating the right degree to which pathological version should be corrected .
psi will help in the placement of the glenoid component on the best bone stock with the desired alignment .
clear advantages in total knee arthroplasty are the fact that it is very intuitive and effective in placing the components in the desired position , it is attractive to patients because they like a personalised patient - care approach and it increases efficiency in the operating room ( or ) due to the reduced number of instruments required , which leads to reductions in or setup time , turnover time and overall surgical time . while the former may also be observed in psi for shoulder prosthesis , the latter will not necessarily be met .
the added cost of psi manufacturing will need to be judged against the potential benefit in clinical outcomes .
the cost  benefit analysis and long - term clinical studies remain lacking ; these are necessary components in the evaluation of the potential benefits of this alternative .
ng has received financial support outside of the current work in the form of consultancy and lecture fees from zimmer biomet .

Answer:
shoulder arthroplasty is a demanding procedure with a known complication rate .
 most complications are associated with the glenoid component , a fact that has stimulated investigation into that specific component of the implant .
 avoiding glenoid component malposition is very important and is a key reason for recent developments in pre - operative planning and instrumentation to minimise risk.patient-specific instrumentation ( psi ) was developed as an alternative to navigation systems , originally for total knee arthroplasty , and is a valid option for shoulder replacements today .
 it offers increased accuracy in the placement of the glenoid component , which improves the likelihood of an optimal outcome.a description of the method of pre - operative planning and surgical technique is presented , based on the author s experience and a review of the current literature.cite this article : gomes n. patient - specific instrumentation for total shoulder arthroplasty .
 efort open rev 2016;1:177 - 182 .
 doi : 10.1302/2058 - 5241.1.000033 .


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:
chromosomal heteromorphisms are interindividual variation of chromosomes without phenotypic consequences and are detected most frequently in 1q12 , 9q12 , 16q11.2 , yq12 and in the short arms of acrocentric chromosomes ( 13 , 14 , 15 , 21 and 22 ) . in some cases , the enlarged acrocentric p arms of p arm can mask a cryptic translocation and therefore a partial trisomy . here , we report a moroccan 1-year - old girl addressed for suspicion of trisomy 21 having an extremely enlarged p arm in one of her chromosomes 22 .
her length was 78 cm ( 25 centile ) , weight 10 kg ( 25 centile ) and head circumference 46 cm ( 50 centile ) .
she had no psychomotor delay but she had mild dysmorphism including round face , up slanting palpebral fissures , epicanthus , small nose , low - set ears and high arched palate [ figure 1 ] ; echocardiography was normal .
the index propositus having a down - syndrome like facies cytogenetics studies were performed on metaphase chromosome preparations obtained from phytohemagglutinin stimulated lymphocyte cultures according to standard procedures .
chromosome analysis was carried out applying rhg banding at a 400 band level as previously reported and according to the international system for human cytogenetic : nomenclature iscn 2009 . nor staining was realized using standard protocols , as well .
fluorescence in situ hybridization ( fish ) was carried out following respectively manufacturer 's instructions and/or as previously reported .
30 - 19002 ) encompassing two genes dscr4 and dscr8 with 3 markers d21s259 , d21s341 , d21s342 in 21q22.13-q22.2 ( down - syndrome critical region ) and a whole chromosome paint ( wcp ) 21 probe ( cytocell cat n lpp21r ) .
besides a microdissection derived home brew probe specific for all acrocentric short arms and denominated as midi54 and a the centromere - specific probe d14z1/d22z1 , which at the same time hybridizes to centromeres of chromosome 14 and 22 ( kreatech ) .
cytogenetics studies were performed on metaphase chromosome preparations obtained from phytohemagglutinin stimulated lymphocyte cultures according to standard procedures .
chromosome analysis was carried out applying rhg banding at a 400 band level as previously reported and according to the international system for human cytogenetic : nomenclature iscn 2009 . nor staining was realized using standard protocols , as well .
fluorescence in situ hybridization ( fish ) was carried out following respectively manufacturer 's instructions and/or as previously reported .
30 - 19002 ) encompassing two genes dscr4 and dscr8 with 3 markers d21s259 , d21s341 , d21s342 in 21q22.13-q22.2 ( down - syndrome critical region ) and a whole chromosome paint ( wcp ) 21 probe ( cytocell cat n lpp21r ) .
besides a microdissection derived home brew probe specific for all acrocentric short arms and denominated as midi54 and a the centromere - specific probe d14z1/d22z1 , which at the same time hybridizes to centromeres of chromosome 14 and 22 ( kreatech ) .
cytogenetics studies were performed on metaphase chromosome preparations obtained from phytohemagglutinin stimulated lymphocyte cultures according to standard procedures .
chromosome analysis was carried out applying rhg banding at a 400 band level as previously reported and according to the international system for human cytogenetic : nomenclature iscn 2009 . nor staining was realized using standard protocols , as well .
fluorescence in situ hybridization ( fish ) was carried out following respectively manufacturer 's instructions and/or as previously reported .
30 - 19002 ) encompassing two genes dscr4 and dscr8 with 3 markers d21s259 , d21s341 , d21s342 in 21q22.13-q22.2 ( down - syndrome critical region ) and a whole chromosome paint ( wcp ) 21 probe ( cytocell cat n lpp21r ) .
besides a microdissection derived home brew probe specific for all acrocentric short arms and denominated as midi54 and a the centromere - specific probe d14z1/d22z1 , which at the same time hybridizes to centromeres of chromosome 14 and 22 ( kreatech ) .
r banding analysis of the chromosomes from peripheral blood of the propositus revealed a normal karyotype apart from an enlarged short arm for one chromosome 22 inherited from the mother [ figure 2 ] .
thus , the karyotype was reported as 46 , xx , der ( 22 ) add ( 22)(p13 ) mat . applying the nor staining results were quite variable and overall non - informative ( data not shown ) .
a partial r banding karyotype of the propositus ( a ) and her mother ( b ) showing enlarged short arm of one chromosome 22 a probe lsi 21 of the critical region for the down - syndrome critical region and a wcp 21 probe excluded the presence of a cryptic trisomy 21 [ figure 3 ] .
fish using a probe for all acrocentric short arms characterized the additional material on the der ( 22 ) as heterochromatin derived from an acrocentric short arm [ figure 4 ] .
therefore , according to cytogenetic and molecular cytogenetic characterization the karyotype was 46 , xx,22ph+++ mat .
metaphases hybridized with down - syndrome critical region probe lsi 21 ( a ) and whole chromosome paint ( wcp ) for chromosome 21 ( b ) . ( a )
( b ) wcp 22 revealed a complete hybridization of the two long arms of chromosome 21 .
neither der 22 nor other chromosomes revealed signal for any of the two probes the short arm of the chromosome 22p++ on the right was completely stained by a probe specific for the acrocentric short arm ( midi54 ) indicating its heterochromatic nature
cytogenetic and fish investigation of the propositus excluded ( cryptic ) trisomy 21 as already reported in down - syndrome like syndrome phenotypes .
instead of clarifying the genetic reason of the clinical problems in this specific case unexpectedly a familial 22ph+++ was detected and further characterized .
uninformative results as seen after nor silver staining was reported by some authors as well , previously .
thus , nowadays fish analysis is more straightforward for the characterization of heteromorphisms in general and acrocentric short arm variants in special .
this kind of molecular cytogenetic analysis also enables to distinguish heteromorphic variants from partial trisomies due to cryptic translocations .
most likely heterochromatin loss or gain are not causative for acquired or inherited disorders , even though such relations still are discussed . to the best of our knowledge ,
this special here reported kind of chromosome 22 short arm enlargement , leading ro ~1.5 larger size than the normal  long arm
fish should always be used to resolve similar situations involving cytogenetic aberrations within the short arms of acrocentric chromosomes .
further follow - up of the propositus may allow us to have more clinical information and making some correlations between this heteromorphism and/or other genetic changes below the cytogenetic resolution and the phenotype of the patient .

Answer:
chromosomal heteromorphisms are described as interindividual variation of chromosomes without phenotypic consequence .
 chromosomal polymorphisms detected include most regions of heterochromatin of chromosomes 1 , 9 , 16 and y and the short arms of all acrocentric chromosomes . here
 , we report a girl with down - syndrome such as facies and tremendously enlarged short arm of a chromosome 22 .
 fluorescence in situ hybridization ( fish ) with a probe specific for all acrocentric short arms revealed that the enlargement p arms of the chromosome 22 in question contained exclusively heterochromatic material derived from an acrocentric short arm .
 parental studies identified a maternal origin of this heteromorphism .
 cryptic trisomy 21 of the down - syndrome critical region was excluded by a corresponding fish - probe . here
 , we report , to the best of our knowledge , largest ever seen chromosome 22 short arm , being ~1.5 larger than the normal long arm .


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:
osmotic demyelination syndrome ( ods ) including central pontine myelinolysis ( cpm ) and extrapontine myelinolysis ( epm ) following overly rapid correction of hyponatremia has been well recognized515 ) .
although ods occurring after transsphenoidal resection of pituitary adenoma has been reported occasionally111618 ) , to our knowledge , few preoperative epm cases with pituitary adenoma have been reported14 ) .
unfortunately , the outcomes of patients with ods are often disappointing with high rate of mortality and irreversible neurological deficits5 ) . here
, we report a case of preoperative epm with nonfunctional pituitary macroadenoma who made a great clinical recovery after supportive therapy and transsphenoidal adenoma resection .
a 38-year - old man was admitted to our hospital in december 2012 because of nausea , malaise , altered mental status , behavioral disturbances , dysarthria and dysphagia .
the patient had been well until 2 months before admission , when nausea and malaise developed .
his wife also reported that the patient had two episodes of transient loss of consciousness .
he was sent to the emergency department of an outside hospital . at presentation , the patient had no sign of dehydration like poor skin turgor , orthostasis or decreased urine output , nor sign of volume overload including peripheral edema , ascites or elevated jugular vein pressure .
serum sodium of 102 mmol / l , potassium of 3.9 mmol / l and phosphate of 1.08
mmol / l were reported . the complete blood count and the remainder of metabolic panel including
intravenous hypertonic saline was given with an average correction rate of 8 mmol/24 h. despite slow rate of correction , neurologic symptoms including restlessness and irritability developed . in the following days , the patient developed apathy , confusion and obtundation , followed by dysarthria , dysphagia , paraparesis , behavioral disturbances and disorientation .
endocrine studies revealed a serum cortisol concentration ( 8 : 00 a.m. ) of 62.4 nmol / l ( normal , 138635 nmol / l ) , plasma adrenocorticotrophin ( acth ) of 1.03 pmol / l ( normal , 2.217.6 pmol / l ) .
miu / l ) ; serum free thyroxine ( ft4 ) was 6.91 pmol / l ( normal , 11.522.7 pmol / l ) , and serum total thyroxine ( t4 ) was 43.0 nmol / l ( normal , 65155
cranial magnetic resonance imaging ( mri ) was performed and a pituitary macroadenoma ( fig .
one week before admission , mri was repeated and epm was detected at bilateral basal ganglion and thalamus ( fig .
the patient was referred to our hospital because of persistent neurologic deficits . on physical exam , he was unresponsive to verbal or pain stimuli .
hormone studies showed normal atch , cortisol , tsh , t4 , and ft4 , decreased growth hormone and insulin - like growth factor 1 , normal prolactin , decreased gonadotrophin ( follicle - stimulating hormone and luteinizing hormone ) , estrogen and testosterone .
the patient had several episodes of restlessness and agitation with shouting and fighting lasting 10 minutes every day .
the decision of surgery was made then based on the improved general state of the patient and the intent to remove the underlying cause of hypopituitarism and hyponatremia .
pathologically , the mass was confirmed to be nonfunctional adenoma by hematoxylin and eosin ( h&e ) staining and immunohistochemical examination .
pseudorosette patterns were found on h&e staining and nuclear division was less than one per 10 high power field .
the tumor cells were scattered positive for p53 and ki-67 . and ki-67 index was < 1% .
the immunostainings for acth , fsh , lh , prl , tsh and gh were negative .
recent hormone studies showed normal level of acth , cortisol , tsh , ft4 and t4 .
the patient was able to resume his work as a bank accountant three months after the surgery .
the latest follow - up mri was obtained 7 months postoperatively , and these images showed demyelination at bilateral basal ganglions and thalamus resolved and pituitary adenoma resected ( fig .
among various etiologies of hyponatremia , endocrine disorders , including adrenal insufficiency and hypothyroidism , are uncommon causes which may be overlooked1712 ) .
while hyponatremia can be caused by hypopituitarism , severe hyponatremia occurring as the presenting manifestation of pituitary adenoma is rare8 ) . at the onset of hyponatremia ,
given the endocrine abnormality and histology - confirmed pituitary adenoma , we propose that secondary adrenal insufficiency and hypothyroidism resulting from hypopituitarism was the underlying cause of his hyponatremia .
however , demyelination can occur even with this correction rate ( as in our case ) , especially in those with other ods risk factors5 ) .
except for the rate of correction , serum sodium concentration at presentation and the duration of the hyponatremia are also important risk factors . on presentation ,
our patient had been symptomatic for 2 months and the serum sodium level was as low as 102
therefore , patients with more than one risk factors for ods may still be at risk for development ods at " normal " rates of correction and may require slower rates . if ods does develop despite the steps taken to avoid overly rapid correction , effective management is rare .
although reintroduction of hyponatremia , plasmapheresis and corticosteroids has been used , most evidence comes from animal models and data in humans are limited to case reports2513 ) .
a more recent review of 32 german patients with ods showed a much better outcome with only 30% having irreversible and incapacitating neurological deficits9 ) .
this review suggests that patients with ods can survive if the nonspecific secondary complications of transient illnesses such as aspiration pneumonia , deep venous thrombosis , and pulmonary embolism can be avoided .
some patients with ods can recover function after prolonged periods of severe neurologic impairment59 ) .
as in our case , the patient had developed progressive neurologic symptoms for two months on admission to our hospital .
the patient was able to resume the job as a banking account after surgery , indicating complete recovery from neurologic and cognitive deficits .
therefore , supportive therapy should be continued for at least six to eight weeks before concluding that the deficits are irreversible .
surgery is the ultimate effective treatment for nonfunctioning adenoma , which not only removes the underlying cause of hypopituitarism , but also reverses or prevents vision impairment . according to a systemic review and meta - analysis evaluating the outcome of surgical treatment for nonfunctioning pituitary adenomas , pituitary hypofunction
improved in as many as 30 percent after surgery10 ) . while for patients with epm , appropriate surgical timing of adenoma resection is of great importance .
neurologic deficits of preoperative epm such as decreased level of consciousness , paraparesis , dysarthria and dysphagia , posed great challenge to the transsphenoidal operation of pituitary adenoma .
risk of complications such as aspiration , respiratory failure , and deep vein thrombosis is much higher than patients without neurologic deficits49 ) . to minimize the risk of surgery and to remove the underlying cause of hyponatremia
, we selectively arrange the operation after dysphagia and dysarthria resolved , and the patient became ambulant and able to obey simple commands .
we report a case of preoperative epm with nonfunctional pituitary macroadenoma who made a great clinical recovery after supportive therapy and transsphenoidal adenoma resection .
more cases are required to clarify the prognosis of ods and identify the factors associated with better outcome .

Answer:
few preoperative extrapontine myelinolysis ( epm ) cases with pituitary adenoma have been reported .
 no such case had long follow - up to see the outcome of epm .
 we reported a 38-year - old man complaining of nausea , malaise and transient loss of consciousness who was found to have severe hyponatremia .
 neurologic deficits including altered mental status , behavioral disturbances , dysarthria and dysphagia developed despite slow correction of hyponatremia .
 endocrine and imaging studies revealed hypopituitarism , nonfunctional pituitary macroadenoma and extrapontine myelinolysis .
 transsphenoidal surgery was performed after three weeks of supportive therapy , when neurological symptoms improved significantly .
 the patient recovered function completely 3 months after surgery .
 our case indicates that outcome of epm can be good even with prolonged periods of severe neurologic impairment .


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:
for millions of years , daily salt ( sodium chloride ) intake in man was about 1 g . then recently , about 10,000 years ago , salt intake increased by about ten - fold   because of the practice of using salt as a food preservative .
it allowed former nomads to settle , grow grain and preserve foodstuffs over long periods .
over the last few millennia , humans got used to the taste of salt and enjoyed the benefits of non - perishable food .
genetically , humans are well - equipped with mechanisms that retain even tiny amounts of salt , a prerequisite for survival at those times when salt was scarce and intake was low . in keeping with this background ,
humans have less efficient excretory mechanisms when challenged with large salt loads , and the limiting factor is the rate of renal salt excretion . if salt intake exceeds the kidneys ability for salt excretion , then salt is deposited in the body , which , in synergy with aldosterone , affects heart , blood vessels   and kidneys .
it is estimated that at least 30% of the world 's population develop hypertension ( elevated blood pressure ) when exposed to a high salt diet . in the past
, salt sensitivity was thought to be the result of kidney malfunction , i.e. on the imbalance between salt input and salt output .
however , recent observations suggest that the vascular system may also play an important role in this imbalance .
more than 20 years ago , it was shown that the vascular endothelium expresses sodium channels similar to those in renal epithelia .
some years later , it was demonstrated that sodium channel function in endothelium was regulated , much as it is in the kidney , by the mineralocorticoid hormone aldosterone .
the fact that the vascular system is also a potential target for aldosterone led to a paradigm shift in so far as the attention was no longer directed solely to the kidney but also to the vascular system [ 13 - 20 ] .
currently , there are far more data on the pathophysiology of aldosterone affecting vascular function than on the  normal  vascular physiology of this steroid hormone [ 21 - 33 ]
. sodium and aldosterone synergistically act on the endothelium . at cellular level , small changes in plasma sodium concentration can have a large impact on endothelial function as long as aldosterone ( or aldosterone receptor function ) is available .
even a 5% increase in plasma sodium concentration mechanically stiffens endothelial cells by about 25% , leading to cellular dysfunction ( decreased nitric oxide release / increased vascular smooth muscle tone ) .
a major component of this high sodium sensitivity is the sodium channel in the endothelial plasma membrane , which is identical to the epithelial sodium channel cloned from renal tissue .
this channel allows sodium to enter the endothelial cells   and , by yet unknown mechanisms , turn off endothelial nitric oxide synthase activity .
do these in vitro experiments translate into the in vivo setting and explain how plasma sodium as such affects blood pressure ?
this question is not easy to answer since changes in plasma sodium are usually accompanied by changes in osmolality , which may mask any direct action of sodium .
however , a recent study properly corrected for any changes in osmolality , shows that there is indeed a marked alteration in blood pressure observable when plasma sodium is manipulated .
similarly , blood pressure in dialysis patients is known to decrease when sodium concentration in the dialysate is lowered .
furthermore , small but significant changes in plasma sodium , paralleled by concomitant changes in blood pressure , are known to occur in humans during acute or chronic salt intake . finally , there is experimental evidence that the brain may be involved in the sodium - triggered increase of blood pressure .
blaustein and colleagues postulated an interesting hypothesis , namely that high sodium in the cerebrospinal fluid triggers the secretion of endogenous ouabain in the hypothalamus and suprarenal glands .
endogenous ouabain acts in the brain , increasing sympathetic nerve activity , but also acts on blood vessels .
both endogenous ouabain actions lead to vasoconstriction and increase in blood pressure . for obvious reasons , this more complex mechanism , involving different organs ,
most recently , the endothelial surface layer facing the blood stream has become a focus of interest [ 46 - 54 ] .
this soft layer , termed endothelial glycocalyx , is a negatively charged biopolymer known to preferentially bind sodium .
it has been calculated that about 700 mg of sodium can be transiently bound to the endothelial glycocalyx in the human body , which is about the amount contained in a single meal .
interestingly , the sodium buffering capacity of the endothelial glycocalyx is severely damaged by excessive sodium intake over time , leading to a significant reduction of the negatively charged heparan sulphate residues in the endothelial glycocalyx .
these observations led to a new concept of vascular sodium permeability , namely that two ( more or less ) permeable barriers determine the rate of sodium elimination after a salty meal .
one barrier is the endothelial plasma membrane , with a variable sodium permeability depending on the abundance of epithelial sodium channels .
the other barrier , located on the surface of the endothelium , is the endothelial glycocalyx that transiently buffers ingested sodium   and , thus , controls access to the epithelial sodium channels ( figure 1 ) . sodium channel activity and glycocalyx function are inversely related to each other . a plasma sodium concentration in the high - physiological range ( > 140 mm ) reduces the negatively charged heparan sulphate residues of the endothelial glycocalyx , increasing the amount of sodium reaching the endothelial sodium channels , which in turn makes the channels more active .
the overall effect is that the barrier against sodium entry fails under these conditions and the endothelium becomes more permeable to sodium ( figure 2 ) . as indicated above , evidence for a salt - sensitive endothelial glycocalyx and its relationship to endothelial epithelial sodium channels
is based on in vitro experiments and , at best , on ex vivo studies in human tissue ( e.g. human umbilical veins ) . to our knowledge , there are no direct studies in humans .
however , if aldosterone is viewed as a hormone that facilitates sodium retention and epithelial sodium channel expression in the vascular endothelium , then a link between salt and glycocalyx , albeit indirect , becomes visible .
clinical research often describes potentially important phenomena in the human without a mechanistic model . in this case , a mechanistic model based on in vitro experiments is available first , and it will be up to clinical research to test it in the human . this state of vascular function is associated with low daily sodium intake , and/or low aldosterone and/or favorable genetics .
this state of vascular function is associated with high daily sodium intake , and/or high aldosterone and/or unfavorable genetics .
after a salty meal , the translocation of sodium from the blood into the interstitium is delayed by the significant buffering capacity of the endothelial glycocalyx .
sodium will reversibly bind to / dissociate from the endothelial glycocalyx binding sites and , thus , can be readily excreted via the kidneys .
excessive sodium intake over time will damage the endothelial glycocalyx and lead to a decrease in its sodium buffering capacity because of the loss of negatively charged heparan sulphate residues .
following that , sodium gains direct access to the " unprotected " epithelial sodium channels .
thus , in addition to the paracellular transport route ( i.e. sodium transport between endothelial cells along its chemical gradient ) , sodium uses the transcellular pathway for entering the large extracellular space ( about 30% of body weight ) .
there , sodium is bound reversibly to the extracellular matrix [ 59 - 63 ] .
after the ingested sodium has spread throughout the body , the plasma sodium concentration decreases .
now , sodium starts diffusing back into the vascular bed ( along its chemical gradient directed from interstitium to blood ) and will finally be excreted by the kidneys ( figure 2 ) .
this  detour of sodium " through the whole organism delays renal sodium excretion significantly . in the meantime ,
a sodium load from the next salty meal may arrive and so on , leading over time to sodium accumulation in the organism .
vascular salt sensitivity can be defined as the ratio of " endothelial sodium channel activity over endothelial glycocalyx sodium buffer capacity " . it should be noted that vascular salt sensitivity is not thought to be exclusively  congenital  [ 8,64 - 66 ] but could most likely be influenced ( among other yet - unknown factors ) by the amount of ingested salt and by endogenous aldosterone .
as salt sensitivity correlates positively with sodium channel activity in the endothelium , the blockade of these channels by amiloride analogues should help in identifying individuals with a high sensitivity to salt .
the test is described in general terms in figure 3 ( see figure legend and , for more details , see ) .
the four cylinders symbolize the vascular system . after an acute na load ( 5 g nacl orally ) , with and without addition of an epithelial sodium channel blocker ( two separate sessions ) , blood pressure
low vascular sensitivity is indicated by a  ~ zero , high vascular sensitivity is indicated by a  > zero .
the endothelial glycocalyx appears to be a key structure for regulating body sodium . in vitro studies
show that the quality of this biopolymer layer is determined by the abundance of its electrical negative charges .
loss of these surface charges renders the endothelial surface vulnerable to unwanted intruders , among them excessive sodium .
we look forward to clinical research that will hopefully confirm these results in vivo in humans and substantiate the mechanism behind the protective effect of a low salt diet on the cardiovascular system .

Answer:
excessive amounts of salt in food , as usually consumed worldwide , affect the vascular system , leading to high blood pressure and premature disabilities .
 salt entering the vascular bed after a salty meal is transiently bound to the endothelial glycocalyx , a negatively charged biopolymer lining the inner surface of the blood vessels .
 this barrier protects the endothelium against salt overload .
 a poorly - developed glycocalyx increases the salt permeability of the vascular system and the amount of salt being deposited in the body , which affects organ function .
 a simple test system is now available that evaluates vascular salt sensitivity in humans and identifies individuals who are at risk of salt - induced hypertension .
 this short review aims to discuss how the underlying basic research can be translated into medical practice and , thus , meaningful health outcomes .


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:
Synergistic catalysis: cis-cyclopropanation of benzoxazoles

Paper sections:
Introduction

In the last years huge efforts have been made to develop new activation modes in order to synthesize complex scaffolds in an enantiopure form. The most common approach has been the development of new catalysts to activate an "unreactive" compound A that will react with a highly reactive compound B to render C. However, recently a new approach pushes the boundaries of organic chemistry: synergistic catalysis, where the concurrent activation of both reactants allows the use of both unreactive substrates to form a new C-C bond. Earlier examples of synergistic catalysis merging transition metals and organocatalysts can be found in the pioneering works of Cordova who reported the a-allylic alkylation of unactivated aldehydes with allyl acetates by using both enamine and Pd chemistry. 1 Later, Zhang reported an efficient asymmetric variant by using Cordova's synergistic strategy and Pd catalysts with C 2 -symmetrical chiral metallocene ligands. 2 MacMillan and Sibi reported examples of asymmetric synergistic catalysis based on enamine catalysis and metal-bound electrophiles. 3 On the other hand, synergistic catalysis with a,b-unsaturated carbonyl compounds has attracted much recent interest. The works of Cordova in b-silylation, b-arylation or b-borylation by using iminium and transition-metal activation demonstrated the importance of this approach. 4 In this area, List also reported excellent results for allylation and Overman rearrangement reactions by using phosphoric acid derivatives and transitionmetal catalysts. 5 Very recently, our research group became interested in synergistic catalysis. 6 Our research focuses on the development of methodologies for the stereoselective synthesis of alkyl benzoxazoles based on the concurrent activation of alkyl benzoxazoles by metal-based Lewis acid catalysis (inspired by the pioneering work of Lam) 7 and organocatalytic activation of several electrophiles. 8 It is well known that one of the most important concerns of this approach is the possible autoquenching of both catalysts. However, by careful choice of the catalysts and the reaction conditions, we successfully developed the addition of alkylbenzoxazoles to Morita-Baylis-Hillman (MBH) carbonates and enals in good yields and stereoselectivities (Fig. 1).

Despite signicant progress and the advantages of using two unreactive substrates, synergistic catalysis presents a clear limitation in terms of range and scope: all these reactions generate only 1 C-C bond, making this approach more expensive and contrary to atom economy (2 catalyst for only 1 bond formation). This drawback attracted our interest and we propose to overcome this limitation by a carefully designed cascade reaction based on a synergistic approach. In our earlier examples we successfully combined metal Lewis activation of azaarenes with iminium catalysis, with good results but with some limitations such as moderate enantioselectivities and low diastereoselectivities due to an epimerization process. 6b We thought that a good option to develop a cascade reaction based on a synergistic approach and, at the same time, to limit the drawbacks of our previous work, should be the design of an organocascade reaction that could trap the enamine "in situ", rendering a more complex scaffold with high stereoselectivity using the same catalytic system in order to push the boundaries of synergistic catalysis by forming 2 C-C bonds using 3 catalytic cycles.

Due to our experience in organocascade reactions, we envisioned that a cyclopropanation using chloro-alkylbenzoxazoles and enals will full the requirements as a proof of concept of this approach and at the same time will allow us to synthesize an important scaffold in organic chemistry.

Cyclopropanes 9 are structural motifs widely present in naturally occurring compounds, including terpenes, fatty acid metabolites, pheromones, etc., 10 and in pharmaceutical compounds with a large spectrum of biological properties. 11 Cyclopropanes are also useful as synthetic intermediates that can undergo ring-opening or ring-expansion reactions to form a range of functionalized products. 12 Asymmetric cyclopropanation reactions have fascinated organic chemists for decades and exciting advances have recently been reported; however, the development of new methodologies for the stereoselective synthesis of cyclopropanes is still a major challenge. In the literature, several approaches for their enantioselective synthesis are reported, for example, the venerable Simmons-Smith cyclopropanation, 13 organometallic methodologies that use Cu, Rh and other transition-metal complexes 14 or, with the advent of organocatalysis, several Michael-initiated ring-closing domino reactions, etc. 15

Results and discussion

To show the viability of the present reaction initially we studied the addition of chloro-alkylbenzoxazole 1a with cinnamaldehyde. The proposed synergistic mechanism is shown in Fig. 2.

As shown in Fig. 2, we envisioned that the metallic Lewis acid would interact with the alkylbenzoxazole 1 by coordinating to the nitrogen atom of 1 and increasing the acidity of the proton in the methylene position. The co-catalyzed mechanism involves the stereoselective addition of palladium enolate (9) to chiral iminium intermediate 6, followed by an intramolecular 3exo-tet cyclization. As suggested by Lam, 7 at rst a coordination of the palladium to the benzoxazole occurs, followed by deprotonation by the external base leading to species Aer a short screening we found that the best conditions were MeCN as a solvent, Pd(OAc) 2 as a Lewis acid, Jorgensen-Hayashi catalyst (I) as secondary amine and 2,6-lutidine as stoichiometric base. To our delight the reaction rendered the nal cyclopropane rings in excellent yields and stereoselectivities. The study of NMR spectra conrmed that the major diastereomer obtained in the cyclopropanation reaction has a cis disposition between the aryl ring and the benzoxazole substituent (see ESI †). This result adds, without any doubt, an important value to the present methodology. The synthesis of cis di(hetero)aromatic cyclopropanes via an intermolecular reaction is very challenging. This unusual cis conguration is difficult to obtain by any other enantioselective methodology that forms the C-C bond bearing both aryl groups. Only Mezzetti 16 and Katzuki 17 using ruthenium and iridium catalyst got the cis compound as a major diastereomer with excellent results in the reaction of styrenes with diazoacetates. Formally, the methodology reported in this paper is stereocomplementary with the MacMillan cyclopropanation that renders trisubstituted cyclopropanes in a trans conguration. 18 With the optimized reaction conditions in hand, we investigated the substrate scope of the reaction with respect to enal derivatives. As shown in Scheme 1, the reactions afford the corresponding formyl cyclopropanes in good to excellent yields with moderate to good diastereoselectivities and excellent enantioselectivities in the major diastereomer. Remarkably, in all the examples the major diastereomer could be easily isolated by column chromatography while the other two diastereomers observed, usually are non-separable mixtures. All the diastereomeric ratios are from the nal isolated products.

The reaction is compatible with several substituents in the aromatic ring. Electron-withdrawing groups like 4-NO 2 (4d) or 4-CN (4f) render the nal cyclopropane in good yields (79% and 63%), good diastereoselectivities and excellent enantioselectivities. Several halides were also tested in the reaction giving similar results, for example 4-Br (4b), 4-Cl (4c) and 4-F (4e) render the predicted formyl cyclopropane in good yields and diastereoselectivities (86-70% yield and up to 3 : 1 d.r.) and exceptional enantioselectivities (up to 99% ee). When the most sterically demanding 2-Br cinnamaldehyde derivative was used, the formyl cyclopropane (4h) was obtained with good yields and excellent enantioselectivity in the major diastereomer but with lower diastereoselectivity. To our delight, when we tested the enal derived from glyoxylate, the reaction rendered the cyclopropane (4i) with good yield and excellent diastereoselectivity (only one diastereomer) but lower enantioselectivity. This could be due to an epimerization at C3 position of the product during the reaction.

As shown in Fig. 3, when an ester moiety is placed in C3, this proton becomes quite acidic and could undergo epimerization with the base to form the most stable trans diastereomer, which would be stabilized by a coordination of the metal with the nitrogen from benzoxazole and the carbonyl compound from the ester. If this epimerization occurs, the outcome of the reaction will be one diastereomer with moderate enantioselectivity as observed by us. Finally, the only limitation of the present methodology is with the aliphatic enals that gave complex crude mixtures when subjected to the reaction conditions.

The relative conguration of the minor diastereomer was conrmed by X-ray crystallography (Fig. 4), while the relative conguration of the major diastereomer was inferred by NMR spectroscopy (see ESI †).

The absolute conguration of the two diastereomers was determined to be 1R,2R,3S for the major diastereomer 4d (using (S)-I as catalyst) and 1R,2R,3R for the minor diastereomer 4d 0 (using (R)-I as catalyst) by TD-DFT simulation of the Electronic Circular Dichroism (ECD) spectra (Fig. 5 and ESI †). 19 This absolute conguration and diastereoselectivity of the major diastereomer is in agreement with the mechanism proposed and with the previous works done with this type of catalysts, where the stereochemistry at b-position of the enal is perfectly controlled by catalyst (I). 15 The relative and absolute conguration of the minor diastereomer could be rationalized by the reaction with the (Z)-palladium enolate.

Next, we investigated the substrate scope of the reaction with respect to the benzoxazole derivative 1. Several benzoxazole derivatives were tested (Scheme 2) and the presence of electronwithdrawing groups in the azaarene ring was crucial for the   reactivity. Cl-substituted benzoxazole rendered the nal product 5a, 5e and 5f with good yields, good stereoselectivities and excellent enantioselectivities. When the benzoxazole had a -NO 2 group at a different position (5b and 5d), slightly lower yields were observed but good diastereoselectivities and excellent enantioselectivities were obtained. Finally, changing the electron-withdrawing -NO 2 group to an ester group rendered the nal product 5c in excellent yield, good diastereoselectivity and excellent enantioselectivity. The only limitation, as previously noted in our previous reports on synergistic catalysis, 6a,b is that an electron-withdrawing group must be present on the benzoxazole ring. Probably, the electron-withdrawing group decreases the pK a value of 1 and allows the deprotonation and the subsequent reaction.

Conclusions

In summary, we have demonstrated that synergistic catalysis can be applied to the development of a cascade reaction by developing a highly enantioselective cyclopropanation of enals with chloro-alkylbenzoxazoles. For the rst time, the metal activation of azaarenes was combined with an organocatalytic cascade reaction, pushing the boundaries of this synergistic approach. Two different catalytic cycles, (i) the metallic Lewis acid activation of azaarenes and (ii) the secondary amine activation of enals, worked in accord to afford the nal products in good yields, with excellent enantioselectivity and good diastereoselectivity. Moreover this reaction gives access to cis cyclopropanes that are difficult to obtain by any other method. The mechanistic studies, synthetic applications and development of new organocascade reactions based on this concept are currently ongoing in our laboratory.

Answer: In the present paper we report our latest efforts in pushing the boundaries of synergistic catalysis. We propose the use of 3 different catalytic cycles working in concert for the formation of cis cyclopropane derivatives of benzoxazoles with excellent stereoselectivities. This is the proof of concept that synergistic catalysis could be successfully used in cascade reactions.


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:
Synthesis and evaluation of cyclic sulfite diesters as sulfur dioxide (SO2) donors

Paper sections:
Introduction

Sulfur dioxide (SO2) is an environmental pollutant that is also produced during metabolism of sulfur containing amino acids [1] as well as hydrogen sulfide (H2S), which is known to mediate a number of cellular processes. [2] The known vasodilatory effects of SO2 in animal models suggest possible signaling roles for this gas as well. [3] SO2 is also used in the food industry as a preservative and an anti-bacterial agent. [4] At elevated levels SO2 is known to cause biomacromolecular damage and cell death; [5] these damaging effects are perhaps responsible for the anti-bacterial properties of this gas. However, due to the limited understanding of molecular mechanisms of action of this gas, reliably producing [6] and detecting SO2 within cells are necessary. While there are numerous probes for SO2, biological studies have thus far relied on gaseous SO2 or a complex formulation of inorganic sulfites. [7] Both methods may not be well suited for enhancing SO2 within cells and offer no temporal control over SO2 release. Furthermore, they are useful for studying effects of SO2 as a single dose, which is unsuitable for study of prolonged exposure. Thus, the chemical biology of SO2 remains largely uncharacterized. 15 Our laboratory has developed several strategies having different triggers for generating SO2 under physiological conditions using small organic molecules. [8] First, 2,4-dinitrophenylsulfonamides with tunable rates of generation of SO2 when triggered by biological thiols were reported (Scheme 1). The use of thiol is used as a trigger may complicate biological studies as targets of SO2 include biologically relevant disulfides and thiols. [8a, 8b, 9] In a second strategy, a series of benzosultines as SO2 donors with controlled rate of generation of SO2 under physiological condition, having heat as a trigger was reported (Scheme 1). [8c] Although enzosultines are stable as solids, they are not highly suited for prolonged storage at room temperature as stock solutions. In third strategy, benzosulfones were reported as photochemically activated SO2 donors by our group and others (Scheme 1). [8d] These compounds might have limitations associated with the inconvenience associated with using a light source in cellular studies and possibly by intensity of light that was required for SO2 generation. [10] Xian et al. reported sodium benzothiazole sulfonate as water-soluble SO2 donor, having limitation of prolonged half-life (t1/2 = 13 days) at physiological pH 7.4. [11] Recently, SO2 donors, using esterase as a trigger, [8f, 12] and click reaction as a mode of SO2 donation, have been reported by our, and Wang's group (Scheme 1). These strategies rely on the use of cellular enzyme, and bio-orthogonal reaction.

Scheme 1. Reported strategies for generation of SO2 under physiological conditions.

Therefore, new self-emulative SO2 donors which are stable at room temperature and permeate cells to enhance intracellular SO2 could help better understand cellular responses to this important gaseous molecule.

Results and Discussion

1,2-Cyclic sulfite diesters were considered as SO2 donors (Scheme 2). Upon attack by a nucleophile (such as water), a sulfite monoester would be formed, which could spontaneously decompose to produce SO2. Modulating substituents "R" or perhaps the pKa of the leaving group would help tune the rate of substitution by a nucleophile and possibly SO2 release. Here, we report results of synthesis and evaluation of a series of 1,2-cyclic sulfite diesters as SO2 donors. 1,2-diols used for synthesis of 1,2-cyclic sulfite diesters were either commercially available (1 and 2; Figure 1) or prepared by Upjohn dihydroxylation from corresponding olefin by OsO4 mediated dihydroxylation [13] (diols 3-5 and 11; Figure 1) or by nucleophilic ring opening of 4-substituted styrene oxide by 10% aq. K2CO3 solution. The diol 6 and 10 were synthesized from Ltartaric acid, and NaBH4 mediated reduction [14] of (±)-benzoin respectively. The diols 7 and 8-9 were prepared by ring opening of corresponding (±)-phenyloxirane and substituted (±)phenyloxirane, in 10% K2CO3 reflux condition respectively. Various 1,2-cyclic sulfite diesters (12-22) were prepared by the reaction of 1,2-diols with thionyl chloride, triethylamine and imidazole in DCM at 0 °C (Table 1). [15] The cis-1,2-diols 3 and 4, gave an isomeric mixture (depending on sulfoxide orientation) of 14 (1:0.68), 15 (1:0.64) by 1 H NMR. [16] The diols 5, 6 and 11 afforded mixture of diastereomers of 16, 17 and 18 in the ratios (depending on chirality of sulfoxide), 16 (1:0.95), 17 (~1:1) and 22 (1:0.86) by 1 H NMR. The racemic 1,2-diols 7-10 afforded mixture of diastereomers for 18-21.

The aforementioned derivatives 12-22 were evaluated for SO2 release in pH 7.4 phosphate buffer. First, ethylene glycol derivative 12 was incubated at 37 °C in pH 7.4 buffer for 30 min. The reaction was monitored for SO2 generation by ion chromatography equipped with an ion conductivity detector; [8b] SO2 was quantified as sulfite, SO3 2-. After 30 min, 12 gave 45% of SO2 (Table 2, entry 1). The pinacol derivative 13 produced negligible amounts of SO2 and a 2% yield was recorded (Table 2, entry 2). These results suggest that increasing sterics on the carbon bearing the sulfite functional group reduced the propensity for decomposition of the compound supporting direct displacement at the carbon, which involves formation of a sulfite monoester, which in turn rapidly rearranges to produce SO2 and an alcohol (Scheme 2) Scheme 1. Sulfite diesters can decompose in pH 7.4 buffer to produce SO2. In the cases of 12-15, nearly similar pKa values for the alcohols implies that any difference in SO2 yields must be due to increased steric hinderance at the carbon bearing the sulfite ester. The diesters 12, 14 and 15 gave SO2 yields > 20% after 30 min, whereas pinacol derivative 13 gave 2% of SO2. These results suggest that when leaving group was similar the important determinant of observed reaction rates was sterics supporting the proposed mechanism (Scheme 2). These results are also consistent with previous reports [17] of 1,2-cyclic sulfite diesters undergoing nucleophilic substitution with various nucleophiles such as chloride, azide and (CH3OOC)2HC − at one of the activated carbon atoms (Scheme 2). [17][18] The hydrolysis of cyclic sulfite esters of normal, or cis or trans diols under acidic (cat. H2SO4/HClO4) or basic (2 eq. NaOH) reflux condition, results in sulfur-oxygen bond fission to give corresponding diol without change in stereo-configuration. [17,19] In order to study the electronic effect on decomposition, diesters 16 and 17 were incubated in pH 7.4 buffer and 93% and 98% SO2, respectively were recorded (Table 2, entry 5 and 6). These compounds contain an electron withdrawing substituent as compared to ethylene glycol diester 12. The electron withdrawing nature of the ester enhances electrophilicity of the carbon bearing the sulfite functional group contributing to an increased rate of displacement.

Next, decomposition of derivatives with phenyl substituent 18-21 was carried out. After 30 min, the phenyl derivative 18 gave 73% of SO2 (Table 2, entry 7). The 4-NO2-phenyl derivative 19 on the other hand produced higher amount of SO2 and a 96% yield was obtained (Table 2, entry 8). Incubation of the 4-F-phenyl derivative 20 (Table 2, entry 9) resulted in a nearly similar SO2 yield as that of phenyl derivative 18. The diphenyl derivative 21 gave 83% SO2 after 30 min (Table 2, entry 10). These results suggest that electron withdrawing group on phenyl substituent increases the rate of decomposition, again consistent with a nucleophilic displacement mechanism. Values are for the corresponding 1,2-diol (most acidic proton) calculated using ChemBioDraw Ultra 16.0.

A number of SO2 probes that typically use the distinct nucleophilic properties of sulfite/bisulfite have been developed by various groups. [20] . For example, Sun et al. have reported probe 23 for selective detection of SO2 derivatives HSO3 -/SO3 2in pH 7.4 buffer (Scheme 3). [20c] The probe 23 absorbs at 545 nm and upon reaction with HSO3 -/SO3 2-, a distinct and ratiometric shift to an absorbance at 410 nm (for 24) was observed (see Supporting Information, Figures S1 and S2). A similar UV profile was observed when 23 was reacted with the SO2 donor 17 supporting the intermediacy of sulfite (Figure 2a). The probe 23 fluoresces in the red region and upon reaction with SO3 2-/HSO3it forms green fluorescing adduct 24 (Figure 2b). When 23 was treated with sulfite diester 17, we find a similar shift in emission (Figure 2b). Together, these data independently confirm the ability of 17 to generate SO2 in pH 7.4 buffer.

Scheme 3. Reaction of probe 23 with sulfites

The expected product formed during hydrolysis in buffer is the diol (Scheme 2). In order to confirm this, we incubated 19 in pH 7.4 buffer and monitored the decomposition and formation of 1-(4-nitrophenyl)ethane-1,2-diol 8 (Figure 3). We find nearly complete disappearance of 19 during 30 min with the formation of 8 as the exclusive product (Figure 3) and a nearly quantitative yield of SO2 (Table 2, entry 8). Thus, the decomposition of the sulfite monoester was and SO2 is likely to be generated as soon as the intermediate is produced (Scheme 2). Having established the suitability of cyclic sulfite esters for molecular biology studies, cell permeability as well as the suitability of these compounds for enhancing intracellular levels of SO2 was examined. The ratiometric probe 23 has been previously reported to be suitable for detection of intracellular sulfite/bisulfite. When DLD-1 cells treated with 23 (10 μM), we found a distinct fluorescence signal only in the red channel but not in the green channel (Figure 4A-C). [20c] When cells pre-treated with 23 were exposed to 17 (20 μM), a decrease in fluorescence signal in the red channel with concomitant increase in fluorescence increase in green channel was observed (Figure 4D-F). Under similar conditions, when a similar experiment was conducted with authentic bisulfite, we found a similar profile. [20c] However, an increased concentration of 200 M was necessary to elicit this response whereas with the donor developed in this study, a significantly lower concentration could achieve enhancement of intracellular SO2. Above results suggest the compatibility of cyclic sulfite diesters with cellular nucleophiles. Lastly, a cell viability assay conducted with human cervical cancer cells (HeLa) revealed SO2 donors 17 and 13 were not significant inhibitors of proliferation at 100 μM (see Supporting Information, Figures S3 and S4). Thus, the SO2 donor 17 might find convenient use for studying cellular responses to enhanced reactive sulfur species.

Conclusions

In summary, we report a series of 1,2-cyclic sulfite diesters that: can be easily synthesized; are stable at room temperature; have tunable SO2 release profiles; and are well suited to study effects of enhanced intracellular levels of SO2 and duration of exposure to this reactive species. Together, we present superior alternatives to inorganic sulfites, the most commonly used SO2 donors. Due to the fundamental importance of redox regulation in cellular growth and survival, perturbation of redox homeostasis has emerged as a possible mechanism for the development of new therapeutics. [21] Thus, reliably generating reactive oxygen, [22] nitrogen [23] and sulfur species [8a, 8b, 8e] may have a range of applications including developing small molecule-based inhibitors of against bacteria such as Staphylococcus aureus, [8e, 22e] Mycobacterium tuberculosis [8a, 8b, 22a, 22b] as well as cancer. [24] Experimental Section Synthesis and characterization data for all new compounds and assay protocols.

Answer: Although sulfur dioxide (SO2) finds widespread use in the food industry as its hydrated form, sulfite, a number of aspects of SO2 biology remain to be completely understood. Among the tools available for intracellular enhancement of SO2, most suffer from poor cell permeability and a lack of control over SO2 release. We report 1,2-cyclic sulfite diesters as a new class of reliable SO2 donors that dissociate in buffer through a nucleophilic displacement to produce SO2 with tuneable release profiles. We provide data in support of the suitability of these SO2 donors to enhance intracellular levels of SO2 at an efficiency superior to sodium bisulfite, the most commonly used SO2 donor for cellular studies.


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 relationship between pulp of the tooth and surrounding periodontium was first described in 1964 , and since then the term endo - perio has become an integral part of the dental vocabulary . unfortunately , this term has been used indiscriminately to categorize disease of either periodontal or endodontic etiology , with or without secondary involvement of the other .
it conveniently provides a blanket diagnosis but could be misleading for any such lesion , regardless of its primary etiology .
although the role of pulpal pathology in the etiology of furcation involvement is still unclear , the high incidence of molar teeth with accessory canals supports such an association .
various treatment modalities have been proposed for the treatment of furcation involvement alone including open flap debridement , bio - modification of root surface , and various regenerative procedures including gtr and bone grafts .
bone grafts having a property of osteogenesis , osteoinduction , and osteoconduction have been used in the past .
this case report attempts to utilize a bioactive glass with the property of osteostimulation as bone replacement graft in the treatment of a combined endo - perio lesion with furcation involvement .
the periodontium and pulp have embryonic , anatomic , and functional interrelationship . the relationship between pulpal and periodontal disease
can be traced to embryological development , since the pulp and the periodontium are derived from a common mesodermal source . at the stage of tooth development
, the developing tooth bud pinches off a portion of mesoderm that becomes pulp , while the remaining mesoderm develops into the periodontium .
ectomesenchymal cells proliferate to form the dental papilla and follicle , which are the precursors of the periodontium and the pulp , respectively
. this embryonic development may give rise to an anatomical connection between these two vital structures throughout the life of a tooth .
three main pathways have been implicated in the development of periodontal - endodontic lesions , namely :
 dentinal tubuleslateral and accessory canalsapical foramen
  lateral and accessory canals the most commonly used classification was given by simon et al .

primary endodontic lesionprimary periodontal lesionprimary endodontic lesion with secondary periodontal involvementprimary periodontal lesion with secondary endodontic involvementtrue combined lesion
  primary endodontic lesion primary periodontal lesion primary endodontic lesion with secondary periodontal involvement primary periodontal lesion with secondary endodontic involvement
the periodontium and pulp have embryonic , anatomic , and functional interrelationship . the relationship between pulpal and periodontal disease
can be traced to embryological development , since the pulp and the periodontium are derived from a common mesodermal source . at the stage of tooth development ,
the developing tooth bud pinches off a portion of mesoderm that becomes pulp , while the remaining mesoderm develops into the periodontium .
ectomesenchymal cells proliferate to form the dental papilla and follicle , which are the precursors of the periodontium and the pulp , respectively . this embryonic development may give rise to an anatomical connection between these two vital structures throughout the life of a tooth .
three main pathways have been implicated in the development of periodontal - endodontic lesions , namely :
 dentinal tubuleslateral and accessory canalsapical foramen
  lateral and accessory canals
primary endodontic lesionprimary periodontal lesionprimary endodontic lesion with secondary periodontal involvementprimary periodontal lesion with secondary endodontic involvementtrue combined lesion
  primary endodontic lesion primary periodontal lesion primary endodontic lesion with secondary periodontal involvement primary periodontal lesion with secondary endodontic involvement
a 22-year - old patient reported to the department of periodontics with a complaint of pain in the lower right back tooth region associated with pus discharge since 1 month . on intraoral examination , an intraoral sinus was found to be present in relation with 46 [ figure 1 ] .
a radiograph was taken with a gutta percha cone inserted in the sinus so as to gauge the path of the sinus tract as shown in figure 2 .
iopa also showed widening of periodontal ligament space in relation with the mesial root and radiolucency in the furcation area .
the horizontal probing depth ( hpd ) with naber 's probe and vertical probing depth ( vpd ) with the unc-15 probe were measured which were found to be 6 mm and 4 mm , respectively .
probing was standardized by fabricating an acrylic stent as shown in figures 1 and 3 .
the patient was then referred to department of conservative dentistry to check for tooth vitality .
electric pulp testing was done to check for tooth vitality , which confirmed that the tooth was nonvital .
vpd of 4 mm with unc-15 probe radiograph showing gutta percha when inserted though the sinus tract extending till the mesial root of 46 hpd of 6 mm with naber 's probe treatment planning was done taking into consideration that the tooth was nonvital with a prevailing sinus tract and grade ii furcation involvement as well .
endodontic treatment was taken up first and the patient was followed up for 3 months . at the end of third month , iopa was taken with 46 which showed that the furcation involvement still prevailed [ figure 4 ] .
on clinical examination , it was observed that there was no change in the soft tissue measurements .
therefore , periodontal regenerative surgery using dental putty was planned for treatment of furcation defect [ figure 5 and 6 ] . obturated 46 with radiolucency still evident after 3 month furcation defect with 46 graft material in place at the defect after taking care of asepsis and sterilization the surgery was planned . the area selected for surgery
a full thickness flap was raised at the buccal aspect following intracrevicular incision and vertical releasing incision .
a vertical releasing incision was placed extending into the alveolar mucosa not closer than one tooth to the involved area , i.e. 46 .
full thickness flap was raised till the base of furcation defect followed by split thickness flap beyond the mucogingival junction .
this was done so as to facilitate the coronal positioning of flap , there by resulting in complete coverage of the defect and the material used . after reflection thorough degranulation and debridement was done at the defect area using gracey 's curette # 13 and 14 .
also thorough scaling and root planning was carried out on the exposed root surface area of the defect .
dental putty graft material with osteoconductive and osteostimulative properties was placed and stabilized in the furcation area .
primary soft tissue closure of the flap was done with nonresorbable black silk ( 30 ) suture using interrupted suturing technique [ figure 7 ] .
immediate postoperative the patient was advised proper plaque control , and was prescribed 0.12% chlorhexidine mouthwash for rinsing twice daily .
the sutures were removed 10 days after surgery and the patient was advised to brush at the surgical site using a postsurgical brush for 2 weeks .
the patient was put on regular recall at 1 , 3 , 6 , and 9 months .
the post - op radiograph shows bone fill in the furcation defect as shown in figure 8 .
after taking care of asepsis and sterilization the surgery was planned . the area selected for surgery
a full thickness flap was raised at the buccal aspect following intracrevicular incision and vertical releasing incision .
a vertical releasing incision was placed extending into the alveolar mucosa not closer than one tooth to the involved area , i.e. 46 .
full thickness flap was raised till the base of furcation defect followed by split thickness flap beyond the mucogingival junction .
this was done so as to facilitate the coronal positioning of flap , there by resulting in complete coverage of the defect and the material used .
after reflection thorough degranulation and debridement was done at the defect area using gracey 's curette # 13 and 14 . also thorough
scaling and root planning was carried out on the exposed root surface area of the defect .
dental putty graft material with osteoconductive and osteostimulative properties was placed and stabilized in the furcation area .
primary soft tissue closure of the flap was done with nonresorbable black silk ( 30 ) suture using interrupted suturing technique [ figure 7 ] .
the patient was advised proper plaque control , and was prescribed 0.12% chlorhexidine mouthwash for rinsing twice daily .
the sutures were removed 10 days after surgery and the patient was advised to brush at the surgical site using a postsurgical brush for 2 weeks .
the patient was put on regular recall at 1 , 3 , 6 , and 9 months .
the post - op radiograph shows bone fill in the furcation defect as shown in figure 8 .
when a clinician can not make a definitive diagnosis in the case of an endo - perio lesions , it may be prudent for him or her to initiate either of the treatment modalities and hope for repair .
however , this could be overcome by proper history taking and sequential treatment planning . when the etiology is purely endodontic , calcium hydroxide can be used as an intracanal medicament .
it is an excellent medicament in general , because it is bactericidal , anti - inflammatory and proteolytic ; it inhibits resorption ; and it favors repair .
it is especially effective in endodontic lesions with extensive periapical pathology and pseudo pockets , because of its temporary obturating action which would inhibit periodontal contamination of the instrumented canals via patent channels of communication .
however , lesions which are not true combined lesions , little or no improvement would be seen with the periodontal perspective after endodontic treatment , leaving a very poor and often hopeless prognosis . but with the advent of new regenerative materials
, however , successful periodontal treatment of such lesions has been possible . in this report the pulp vitality test which showed the nonvital nature of the tooth was a pivoting finding suggesting the primary endodontic involvement . generally , in a case of combined endo - perio lesion , an adequate endodontic therapy would result in healing of the endodontic component , and the prognosis would finally depend on the efficacy of periodontal repair / regeneration initiated by either of the treatment procedures . in this case , following endodontic treatment the periodontal lesion did reduce to an extent on radiographic evaluation after 3 months but did not subside completely with no change in the clinical parameters .
it enhances bone formation by ionic dissolution of the ceramic particles such that the silica gel layer forms over the particles on contact with body fluids . over this silica gel layer , a calcium phosphate layer forms , which is quickly converted into a hydroxycarbonate apatite layer
this apatite layer has been shown to be identical to bone mineral and to provide the surface for osteoblast cell attachment and bone deposition .
the results of this case report suggest that bioactive glass in the form of putty resulted in a significant amount of bone fill and reduction in hpd .
this was in accordance with the studies by yukna et al . and anderegg et al .
using bioactive glass showed significant improvement in the clinical parameters when used in furcation defects .
the healing of an endodontic lesion is highly predictable , but the repair or regeneration of periodontal tissues is questionable if associated with it .
endodontic therapy mostly should precede periodontal pocket elimination procedures in the case of a primary endo and secondary periodontal involvement ; however , endodontic therapy would result only in resolution of the endodontic component of involvement and would have a little effect on the periodontal lesion .
therefore a thorough diagnostic examination usually will indicate the primary etiology and , thereby , direct the proper course of treatment plan as presented in this case .
it could also be concluded that bioactive glass in the form of putty which was primarily due to 21% of glycerin added to 69% of bioactive glass and 10% of poly ethylene glycol , made it feasible for manipulation of the material and effective defect fill .
therefore within the limits of this study it can be concluded that bioactive glass is effective as a bone graft substitute in treatment of periodontal component of the endodontic lesion .

Answer:
the success of a combined periodontal and endodontic lesion depends on the elimination of both of these disease processes . in the case of a combined endo - perio lesion , the endodontic therapy results in healing of the endodontic component of involvement while the prognosis of tooth would finally depend on the healing of the periodontal structures .
 this case report evaluates the efficacy of bioactive glass in the management of furcation defect associated with an endo - perio lesion in a right mandibular first molar . a 22-year - old male patient with an endo - perio lesion in the right mandibular first molar
 was initially treated with endodontic therapy . following the endodontic treatment ,
 the furcation defect was treated using bioactive glass in a putty form . at the end of 9 months
 , there was a gain in the clinical attachment level and reduction in probing depth .
 radiographic evidence showed that there was a significant bony fill .


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 a recent issue of critical care , morgan and colleagues present the results of a well - conducted systematic review and meta - analysis of the effect of statin therapy on inflammatory markers after cardiac surgery .
observational evidence suggests that statin therapy may dampen the inflammatory response following exposure to a significant trigger and there is currently much interest in using statins to treat sepsis . in this context cardiopulmonary bypass ( cpb )
is appealing methodologically because it allows the study of preventive interventions [ 4 - 6 ] .
fortunately for patients , mortality following cpb is low , but the methodological downside of this success is that very large trials of low risk patients ( or somewhat smaller trials of higher risk patients ) are needed to show a mortality effect .
the randomised controlled trials included by morgan and colleagues measured post - operative inflammatory markers in adults receiving a statin or placebo prior to cpb . they found that statin therapy may reduce post - cpb inflammation as measured by il-6 , il-8 , c - reactive protein and tumour necrosis factor - alpha .
for example , six of the eight apparently randomised studies provide no information on sequence generation and allocation concealment .
three were unblinded and only two had a low risk of bias ( defined by applying the cochrane risk of bias tool ) .
the median sample size was 43.5 ( range 20 to 200 ) and the confidence intervals around the mean differences in inflammatory markers for individual studies and for the summary estimates were fairly wide .
other studies of inflammatory biomarkers are likely to vary widely between patients and within patients over time , suggesting that analysis of within - patient changes over time may detect differences between treatment groups with more statistical power .
while the meta - analysis does not provide a definitive answer , it raises key methodological issues relevant to sepsis research in general , and to statin research in critical illness in particular .
the methodological quality of many of these studies is variable and frequently the mechanisms ( at both biological and functional levels ) through which benefit are supposed to accrue were not robustly described .
we agree with other authors   that the logical sequence of questions to answer before performing pragmatic mortality trials should be : first , can statins theoretically beneficially modulate the immune response in these patient populations ?
second , do statins beneficially ( and safely ) modulate the immune response and associated physiology ?
third , does the modulated immune response translate into benefit at the level of organ function ? in this regard the critical care research community can learn much from colleagues in rheumatology , cardiology and oncology , who have explored and described mechanistic pathways - paths reliably connecting biological plausibility and effect with organ performance and then outcomes important to patients ( for example , mortality ) ; and developed reliable and validated surrogate endpoints .
morgan and colleagues want to establish whether potential surrogate endpoints ( inflammatory markers ) are modulated , but herein lay the problems .
second , while data from successful ' mortality ' randomised controlled trials may improve our understanding of surrogate outcomes , interventions that improve surrogate markers do not necessarily translate into improved mortality [ 12 - 14 ] .
third , what is the minimum clinically important difference for a biomarker or combination of biomarkers ? how much should individual ( and aggregate ) marker levels differ between groups to translate into clinical benefit ?
lastly , what if ' good ' markers are also suppressed and , indeed , how much inflammation is good for you ?
it is clear that in this relatively new study area the knowledge space is already occupied by poor studies and potentially unreliable data .
we would like to encourage investigators to design studies that are methodologically robust and provide reliable mechanistic data .
icu researchers should work towards developing valid surrogate endpoints to allow robust and reliable translational research , although we acknowledge that previous success at improving organ performance has not always improved outcomes [ 12 - 14 ] .
once validated , these surrogate endpoints should be used to establish the biological effectiveness of new treatments ( and probably some existing ones ) before moving on to pragmatic studies using mortality as outcome measure . without demonstrating first biological and then functional ( for example , organ performance ) effectiveness , we run the risk of wrongly adding statins to the wasteland of icu pharmacotherapy . on the positive side ,
the pleiotropic effects of statins and extensive experience with these agents in cardiology mean that we may be less likely to fall into a trap constructed of an insufficient understating of mechanisms combined with a single - target therapy .

Answer:
statin therapy may prevent an excessive inflammatory response after cardiopulmonary bypass for cardiac surgery . in a recent issue of critical care , morgan and colleagues present data from a well - conducted systematic review and meta - analysis of randomised controlled trials using inflammatory markers as primary outcome measure .
 they find that pre - operative statin therapy , compared with placebo , may reduce various post - operative markers of systemic inflammation ( il-6 , il-8 , c - reactive protein , tumour necrosis factor - alpha ) .
 their ability to make definitive conclusions is limited , however , by the suboptimal methodological quality of the primary studies .
 their review suggests that icu researchers should focus on developing valid surrogate markers and use these to accurately describe the mechanisms and effectiveness of novel therapies before proceeding to large pragmatic trials using mortality as primary outcome .


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:
. an earlier version of this paper was written as part of charlotte khlbrandt 's msc dissertation project at the london school of hygiene and tropical medicine .
ck conducted the literature review , collected and analysed the data , interpreted the results and drafted the paper .
we would like to thank dr alex mold , who co - supervised the msc dissertation and commented on a draft of this paper .
we are also grateful for the wellcome trust 's commitment to cover open access charges .
. an earlier version of this paper was written as part of charlotte khlbrandt 's msc dissertation project at the london school of hygiene and tropical medicine .
ck conducted the literature review , collected and analysed the data , interpreted the results and drafted the paper .
we would like to thank dr alex mold , who co - supervised the msc dissertation and commented on a draft of this paper .
we are also grateful for the wellcome trust 's commitment to cover open access charges .

Answer:
light therapy is still used to treat a number of common diseases in russia .
 the practice is firmly anchored in history : soviet clinical practice was divorced from the emerging field of evidence - based medicine .
 medical researchers were cut off from international medical research and scientific literature , with much soviet scientific activity based on a particular socialist ideology . in this study ,
 the use of light therapy serves as a case study to explore tensions between international evidence - based medicine and practices developed in isolation under the soviet union , the legacy of which is to the detriment of many patients today .
 we used four different search methods to uncover scientific and grey literature , both historical and contemporary .
 we assessed the changing frequency of publications over time and contrasted the volume of literature on light therapy with more orthodox treatments such as statins and painkillers .
 our search found an increasing number and comparatively large body of scientific publications on light therapy in the russian language , and many publications emanating from prestigious russian institutions .
 combined with our analysis of the historical literature and our appraisal of 22 full text articles , this leads us to suggest that light therapy entered mainstream soviet medical practice before the stalinist period and still occupies an important position in contemporary russian clinical practice .
 we propose that this outdated treatment survives in russia in part due to the political , economic and social forces that helped to popularize it during soviet times , and by the seeming justification offered by poorly executed studies .