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:
only 30 - 60 per cent of patients respond properly to treatment with antidepressants , beta - blockers , statins and antipsychotic agents .
approximately two days of prolonged hospital visits are caused by adverse drug reactions ( adrs ) , and , in the usa , about 100,000 deaths are estimated to be due to adrs every year .
these data emphasise an important problem that can be mostly explained by variable pharmacokinetics due , to a large extent , to differences in the activity of cytochrome p450 ( cyp ) enzymes involved in the metabolism of the drugs .
variable metabolism , in turn , can be caused by variation in the cyp genes , as is the focus of the current review .
there are 57 active cyp genes in the human genome , which are divided into 18 families . the first three families ( cyp1 - 3 ) are generally involved in the metabolism of exogenous substances such as drugs , whereas cyp families with higher numbers are usually involved in the metabolism of endogenous substances .
cyp enzymes are responsible for 75 - 80 per cent of all phase i - dependent metabolism and for 65 - 70 per cent of the clearance of clinically used drugs .
variation in cyp genes results in phenotypes classically defined as ultrarapid , extensive , intermediate and poor metabolisers .
an ultrarapid metaboliser ( um ) generally carries duplicated or multi - duplicated gene copies of the same allele , whereas intermediate ( i m ) and poor metabolisers ( pm ) characteristically carry one and two defective alleles ( eg gene inactivation or deletion ) , respectively .
the term extensive metaboliser ( em ) is normally used for subjects carrying two alleles giving normal activity of the cyp enzyme ( also called the * 1 or consensus allele ) .
the metaboliser phenotypes are mainly used for describing drug metabolism , but genetic variation in cyps with endogenous functions , such as in sterol , steroid , bile acid and fatty acid homeostasis , have also been well characterised , some of which give rise to disease states .
cyp3a4 accounts for about 50 per cent of all cyp - dependent drug metabolism , although individuals ' capacity for cyp3a4-mediated drug metabolism is highly variable .
no common genetic variants can account for this variation , despite the fact that 20 different alleles have been described .
by contrast , cyp2c19 and cyp2d6 are highly polymorphic and together account for about 40 per cent of the metabolism of clinically used drugs .
in addition , cyp1a2 , cyp2a6 and cyp2b6 are polymorphic enzymes that significantly contribute to xenobiotic metabolism .
the characterised genetic polymorphism of these enzymes provides a basis for the possibility to adjust drug dosage and choice of drug therapy according to genotype,[4 - 8 ] which includes avoidance of adrs , since polymorphic cyps are frequently the cause of these , either due to the formation of high levels of metabolites or because of decreased metabolism of the parent drug .
important work in the cyp area focused on the identification and characterisation of polymorphic human cyp genes , which , in turn , created the need for a unified nomenclature system .
thus , in 1999 , a nomenclature committee was formed with the aim of creating a platform for present and future allele nomenclature .
thus , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) was launched with the purpose of managing allele designations , facilitating rapid online publication and providing a summary of alleles and their associated effects .
the nomenclature system chosen for the cyp - allele website was based on recognised nomenclature guidelines [ 9 - 13 ] .
currently , the website covers the nomenclature for polymorphic alleles of 29 cyp enzymes and nadph cytochrome p450 oxidoreductase ( por ) ( see table 1 ) .
the cyp2b6 , cyp2c9 , cyp2c19 and cyp2d6 genes are particularly polymorphic , all with a high number of functionally different alleles .
each of the genes at the cyp - allele website has its own webpage that lists the various alleles with their nucleotide changes , molecular and functional consequences in vitro as well as in vivo , and also publications identifying or characterising the alleles .
in addition , links to the national center for biotechnology information ( ncbi ) single nucleotide polymorphism database ( dbsnp ) and papers with allele frequencies are presented .
the number of visits is relatively constant over time , about 36,000 per year , and the website is highly cited in publications in the field of pharmacogenomics .
polymorphic genes covered on the cyp - allele website examples of some important variant alleles are given , as well as representative substrates the designation of an allele ( such as cyp2b6 * 4 ) ideally requires determination of all sequence variations in the gene , although sequencing the intronic regions is generally not necessary . on the website ,
a gene is considered as the sequence from 5 kilobases upstream from the transcription start site to 500 base pairs downstream of the last exon .
if a regulatory element has been characterised at a more distant part of the gene , however , it too is considered to belong to the gene .
all known sequence variations within an allele are described on the cyp - allele website , although new allele numbers are currently only designated for alleles that contain at least one functional variation causing consequences such as amino acid substitutions , translation terminations , splice defects , differential transcription rates etc .
nevertheless , the allele is required to be well characterised regarding linkage or lack of linkage of the consequential snp with other nucleotide variations , including those in exons , intron - exon junctions and flanking regions .
inferring haplotypes by program analyses is generally avoided , although such alleles have occasionally been included on the cyp - allele website . when the characterised sequence variant is found in different constellations with non - causative ( eg silent ) ones ,
the different combinations are defined as sub - alleles and receive letters in addition to the number ( eg cyp2b6 * 4a , cyp2b6 * 4b ) .
when several effective polymorphisms are present on the same allele , however , the allelic number given is based on the polymorphism that causes the most severe consequence , such as a splice defect ( eg cyp2c19 * 2a ) , so alleles that additionally contain sequence variants with less severe effects will share the same allele number , together with an additional letter ( eg cyp2c19 * 2b ) .
combinations of variants that are also present alone and that are considered similarly effective ( eg different amino acid substitutions ) are given unique allele numbers ( eg cyp2b6 * 6 ) .
notably , the earliest described alleles on the website do not follow the nomenclature system , but the allelic designations have remained , for practical reasons . when new alleles are identified , relevant information is sent to the webmaster .
inclusion criteria ( http://www.cypalleles.ki.se/criteria.htm ) involve complete characterisation of the gene sequence , covering exons and exon - intron junctions at the minimum , investigation of linkage with other sequence variants and potential in vitro or in vivo findings .
it is advised that the authors of a manuscript that describes a novel allele contact the webmaster before submission , in order to review the data and assign a new allele name to be used in the manuscript .
usage of star allele designations that have not been approved by the nomenclature committee is strongly discouraged , because of the apparent risk of confusion and of using the same allele name for different variants .
all information sent to the webmaster is kept strictly confidential until publication of the manuscript or until the authors request it to be released .
thus , there are likely to be allele names designated by the cyp - allele website that have not yet been published , further emphasising the importance of refraining from using unauthorised allele names .
the webmaster ( and in rare cases also the editorial and/or advisory board ) reviews the submission to evaluate whether there are enough data to support a new allele designation . only peer - reviewed data are thus published on the cyp - allele website .
papers describing additional characterisation of a known allele -- with respect to , for example , in vitro or in vivo activity -- are also peer reviewed and can be linked to the respective allele on the webpage .
suggestions of papers that should be included with respect to further characterisation of alleles are appreciated .
important work in the cyp area focused on the identification and characterisation of polymorphic human cyp genes , which , in turn , created the need for a unified nomenclature system .
thus , in 1999 , a nomenclature committee was formed with the aim of creating a platform for present and future allele nomenclature .
thus , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) was launched with the purpose of managing allele designations , facilitating rapid online publication and providing a summary of alleles and their associated effects .
the nomenclature system chosen for the cyp - allele website was based on recognised nomenclature guidelines [ 9 - 13 ] .
currently , the website covers the nomenclature for polymorphic alleles of 29 cyp enzymes and nadph cytochrome p450 oxidoreductase ( por ) ( see table 1 ) .
the cyp2b6 , cyp2c9 , cyp2c19 and cyp2d6 genes are particularly polymorphic , all with a high number of functionally different alleles .
each of the genes at the cyp - allele website has its own webpage that lists the various alleles with their nucleotide changes , molecular and functional consequences in vitro as well as in vivo , and also publications identifying or characterising the alleles .
in addition , links to the national center for biotechnology information ( ncbi ) single nucleotide polymorphism database ( dbsnp ) and papers with allele frequencies are presented .
the number of visits is relatively constant over time , about 36,000 per year , and the website is highly cited in publications in the field of pharmacogenomics .
polymorphic genes covered on the cyp - allele website examples of some important variant alleles are given , as well as representative substrates
the designation of an allele ( such as cyp2b6 * 4 ) ideally requires determination of all sequence variations in the gene , although sequencing the intronic regions is generally not necessary . on the website ,
a gene is considered as the sequence from 5 kilobases upstream from the transcription start site to 500 base pairs downstream of the last exon .
if a regulatory element has been characterised at a more distant part of the gene , however , it too is considered to belong to the gene .
all known sequence variations within an allele are described on the cyp - allele website , although new allele numbers are currently only designated for alleles that contain at least one functional variation causing consequences such as amino acid substitutions , translation terminations , splice defects , differential transcription rates etc .
nevertheless , the allele is required to be well characterised regarding linkage or lack of linkage of the consequential snp with other nucleotide variations , including those in exons , intron - exon junctions and flanking regions . inferring haplotypes by program analyses
is generally avoided , although such alleles have occasionally been included on the cyp - allele website . when the characterised sequence variant is found in different constellations with non - causative ( eg silent ) ones ,
the different combinations are defined as sub - alleles and receive letters in addition to the number ( eg cyp2b6 * 4a , cyp2b6 * 4b ) .
when several effective polymorphisms are present on the same allele , however , the allelic number given is based on the polymorphism that causes the most severe consequence , such as a splice defect ( eg cyp2c19 * 2a ) , so alleles that additionally contain sequence variants with less severe effects will share the same allele number , together with an additional letter ( eg cyp2c19 * 2b ) .
combinations of variants that are also present alone and that are considered similarly effective ( eg different amino acid substitutions ) are given unique allele numbers ( eg cyp2b6 * 6 ) .
notably , the earliest described alleles on the website do not follow the nomenclature system , but the allelic designations have remained , for practical reasons .
inclusion criteria ( http://www.cypalleles.ki.se/criteria.htm ) involve complete characterisation of the gene sequence , covering exons and exon - intron junctions at the minimum , investigation of linkage with other sequence variants and potential in vitro or in vivo findings .
it is advised that the authors of a manuscript that describes a novel allele contact the webmaster before submission , in order to review the data and assign a new allele name to be used in the manuscript .
usage of star allele designations that have not been approved by the nomenclature committee is strongly discouraged , because of the apparent risk of confusion and of using the same allele name for different variants .
all information sent to the webmaster is kept strictly confidential until publication of the manuscript or until the authors request it to be released .
thus , there are likely to be allele names designated by the cyp - allele website that have not yet been published , further emphasising the importance of refraining from using unauthorised allele names .
the webmaster ( and in rare cases also the editorial and/or advisory board ) reviews the submission to evaluate whether there are enough data to support a new allele designation .
papers describing additional characterisation of a known allele -- with respect to , for example , in vitro or in vivo activity -- are also peer reviewed and can be linked to the respective allele on the webpage .
suggestions of papers that should be included with respect to further characterisation of alleles are appreciated .
the cyp - allele website is widely used and well acknowledged within the scientific community .
it serves the purpose of a unified and easily accessible nomenclature system for cyp enzymes , as well as for the cyp electron donor por .
the purpose of the cyp - allele website is to facilitate rapid online publication as well as providing a summary of the characteristics of specific alleles .

Answer:
pharmacogenetics affects both pharmacokinetics and pharmacodynamics , thereby influencing an individual 's response to drugs , both in terms of response and adverse reactions . within the area of pharmacogenetics , findings of genetic variation influencing drug levels
 have been more prevalent , and variation in the cytochrome p450 ( cyp ) enzymes is one of the most common causes .
 much of the work concerning sequence variations in cyps aims at finding biomarkers of use for individualised treatment , thereby increasing the treatment response , lowering the number of side effects and decreasing the overall cost of treatment regimens .
 for over ten years , the human cytochrome p450 allele nomenclature ( cyp - allele ) website ( http://www.cypalleles.ki.se/ ) has offered a database of genetic information on cyp variants , along with effects at the molecular as well as clinical level .
 thus , this database serves as an assembly of past , current and soon - to - be published information on cyp alleles and their outcome effects .
 the website is used by academic researchers and companies ( eg as a tool in drug development and for outlining new research projects ) . by providing peer - reviewed genetic information on cyp enzymes ,
 the cyp - allele website has become increasingly popular and widely used .
 recently , nadph cytochrome p450 oxidoreductase ( por ) , the electron donor for cyp enzymes , was included on the website , which already contains 29 cyp genes , hence por alleles are now also designated using the star allele ( por * ) nomenclature .
 although most cyps on the cyp - allele website are involved in the metabolism of xenobiotics , polymorphic enzymes with endogenous functions are also included .
 each gene on the cyp - allele website has its own webpage that lists the different alleles with their nucleotide changes , their functional consequences and links to publications in which the allele has been identified and/or characterised .
 thus , the cyp - allele website offers a rapid online publication of new alleles , as well as providing an overview of peer - reviewed data .


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:
cholelithiasis presented as chronic right back pain in the case discussed in this report . according to the clinical practice guidelines , gallbladder lithiasis is a common condition . around two - thirds of the cases
are asymptomatic , with the most frequent clinical presentation being the presence of attacks of acute abdominal pain . however , chronic right back pain persisting for months as a main symptom is uncommon .
this report presents a patient with right back and subscapular pain for 9 months , demonstrating both biliary lithiasis and chronic cholecystitis .
it is important to take into account the atypical manifestations of a prevalent illness as well as the limitations of the diagnostic tests , since the presence of gallstones can easily be missed or misinterpreted and delay in diagnosis may lead to complications which could worsen the prognosis of the patient .
a 47-year - old male presented with a history of chronic neck pain that had started 10 years back .
he underwent a magnetic resonance ( mr ) which showed cervical canal stenosis of degenerative etiology and also had an episode to self - limited abdominal spasmodic pain that appeared 10 years ago , considered as being functional by the gastroenterologist .
abdominal ultrasonography was performed twice , and both times it was normal . one and a half years ago , the patient had right subscapular and paralumbar back pain at the t10l2 level for 9 months .
he described it as a permanent pain , which persisted throughout the day , with very intense exacerbations , especially in the evening and at night .
these exacerbations usually lasted for 4 - 6 h , worsening on inhalation and sometimes radiating to subcostal and right hemithorax .
the only feature of note on physical examination was the palpation of painful spinal processes from t10 to l2 .
blood analysis showed the level of gamma - glutamyl traspeptidase to be 79 u / l , while all the other laboratory parameters were normal .
abdominal computed tomography ( ct ) showed an extensive hepatic steatosis and a moderately relaxed gallbladder , with no stones observed within thin walls [ figure 1 ] .
abdominal ct : gallbladder without gallstones despite the regular use of analgesics and the rehabilitation treatment that followed , the patient presented a torpid evolution . due to the pain in the right paralumbar area ,
an abdominal ultrasonography was performed , which showed moderate hepatic steatosis and a gallbladder with multiple inner calculi [ figure 2 ] .
on diagnosis of cholelithiasis , a cholecystectomy was carried out , which revealed a gallbladder with a large number of yellow lithiasic structures , thereby confirming an anatomopathological diagnosis of chronic cholecystitis [ figure 3 ] .
the previous pain completely disappeared after surgery and the patient remained asymptomatic 7 months later .
back pain affects 80% of adults at some point of their life and occurs at all ages .
the first objective is to rule out a visceral disorder or a serious potentially life - threatening condition , which occurs in 2.7% of the cases
. back pain may be the manifestation of thoracic involvement as in esophageal disease , pleurisy , aortic aneurysm , or coronary heart disease , or an abdominal process , such as gastrointestinal ulcer , gastric cancer , pancreatic cancer , pancreatitis , or biliary pathology .
only one - third of the cases of gallstones are symptomatic and give an indication for surgery .
the most frequent symptomatic manifestation is episodic upper abdominal pain called biliary colic , with complications such as cholecystitis , acute pancreatitis , cholangitis , or choledocholithiasis being less frequent .
characteristically , this pain is severe and located in the epigastrium and/or the right upper quadrant .
the pain may radiate to the upper back or the right scapula in 60% of the cases and might be associated with nausea or vomiting , usually occurring in the late evening or at night , in 80% of the cases .
one study carried out to characterize the presentation in cholelithiasis reported that all patients described pain in the right upper quadrant of the abdomen , including the epigastrium .
the pain was located in the right subcostal area ( 20% ) and epigastrium ( 14% ) , which radiated to the back in 63% .
in fact , chronic cholecystitis is thought to be a result of a delay in diagnosis .
the test of choice to diagnose cholelithiasis is transabdominal ultrasound , with a sensitivity and specificity greater than 95% for detecting gallstones larger than 4 mm .
abdominal ct scan has a very low sensitivity and gallstones may be visible due to most being isodense .
microlithiasis ( stones <3 mm in diameter ) is not detectable by transabdominal ultrasonography ; however , it may cause complications such as acute pancreatitis . in some patients
the diagnosis can be confirmed by the detection of biliary crystals by microscopic examination of bile collected from the duodenum . in patients with a clinical history of biliary colic with negative transabdominal ultrasonography ,
endoscopic ultrasonography is an important diagnostic tool , since it can detect microlithiasis in a proportion of patients ranging from 41 to 78% .
patients with pain and a negative abdominal ultrasound show an endoscopic ultrasound and/or a positive analysis of the bile .
most of these patients show positive results on cholecystectomy , with resolution of abdominal pain and improvement in their quality of life .
non - vertebral causes such as the presence of gallstones should be considered in patients with back pain .
physicians should be aware of atypical manifestations of common diseases , so as to avoid diagnostic delays .
gallbladder disorders should be taken into account in patients with dull , undefined right back pain , despite a normal physical examination .
abdominal ultrasound should be chosen as the first diagnostic procedure when considering gallstones , since ct scans have a very low sensitivity for their detection . in a patient with a typical clinical report of biliary colic and a negative abdominal ultrasound ,
this was the case of our patient in whom the abdominal ultrasonography was normal 5 years earlier , thereby making correct differential diagnosis crucial .

Answer:
chronic right back pain is a symptom in both biliary lithiasis and chronic cholecystitis
 . ten percent of the population in the world suffers from biliary lithiasis .
 only 20% are symptomatic .
 the first diagnostic test of choice is an abdominal ultrasound .
 when a suggestive clinical sign of biliary colic with negative abdominal ultrasound is identified , we should consider the option of carrying out an endoscopic ultrasound in order to rule out microlithiasis .
 the case discussed in the report presented with chronic right back pain , which is an atypical manifestation of biliary lithiasis and chronic cholecystitis .
 it is important to know about the atypical manifestations of the prevalent illnesses as well as the limits of the diagnostic tests , in order to avoid diagnostic delays which may cause complications that could worsen a patient 's prognosis .
 this case should contribute to the medical knowledge and must have educational value or highlight the need for a change in clinical practice , especially in primary care .


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:
although indomethacin is usually well tolerated , some patients developed gastrointestinal side effects , specially those patients who require long term therapy
. therefore , the use of cyclo - oxygenase-2 specific inhibitors could reduce secondary effects and they are essentially equipotent to indomethacin in vitro and in vivo .
indeed , some reports in the literature indicate the usefulness of the cox-2 inhibitors in the treatment of indomethacin - responsive headaches [ 38 ] .
we report four cases of hemicrania continua and a patient suffering chronic paroxysmal hemicrania completely responsive to cox-2 inhibitors .
a 42  years - old woman had sudden onset of short - lived pains on the left side of her head .
she suffers for a month an intense headache with short attacks ( about 510  min ) but high frequency ( 1018 attacks per day ) .
we put her on indomethacin 25  mg 3  times a day , and in 24  h her hemicranial pain completely disappears . because of legs oedema we discontinued indomethacin and 1  week later the pain returned .
a 56  years - old man present with an 8  month history of a continuous left - sided headache strictly unilateral .
the pain was moderate in intensity but fluctuating ( between 2 and 7/10 vas ) .
the pain exacerbations were associated with lacrimation but not phono , photofobia , nausea or vomiting .
an mri was normal and indomethacin 25  mg 3  times a day was started with completely recovery .
two - month later he started to have gastric symptoms , indomethacin was discontinued and the hemicrania return .
a 78  years - old woman with 1  year history of continuous and strictly left - sided headache , fluctuating in intensity ( 39 in vas ) and accompanied by conjuntival injection and nasal congestion during exacerbation time .
with indomethacin 50  mg 3  times a day the hemicrania disappear , however , she developed disabling subjective tinnitus 1  month later .
we discontinued indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 18  month later .
a 64  years - old woman with 3  years history of right - sided headache , fluctuating in intensity ( 28 in vas ) .
with indomethacin 25  mg 3  times a day the hemicrania disappear , however , the patient suffer gastrointestinal disturbances
. we discontinued indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 10  month later . a 76  years - old man with 6  month history of continuous left - sided headache and facial pain .
after 2  weeks on indometacina he complaint about pyrosis , that persists after omeprazol 40  mg per day .
we decided to discontinue indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 6  month later .
a 42  years - old woman had sudden onset of short - lived pains on the left side of her head .
she suffers for a month an intense headache with short attacks ( about 510  min ) but high frequency ( 1018 attacks per day ) .
we put her on indomethacin 25  mg 3  times a day , and in 24  h her hemicranial pain completely disappears . because of legs oedema we discontinued indomethacin and 1  week later the pain returned .
a 56  years - old man present with an 8  month history of a continuous left - sided headache strictly unilateral .
the pain was moderate in intensity but fluctuating ( between 2 and 7/10 vas ) .
the pain exacerbations were associated with lacrimation but not phono , photofobia , nausea or vomiting .
an mri was normal and indomethacin 25  mg 3  times a day was started with completely recovery .
two - month later he started to have gastric symptoms , indomethacin was discontinued and the hemicrania return .
with celecoxib 200  mg twice a day the hemicrania disappears . after 10  month
a 78  years - old woman with 1  year history of continuous and strictly left - sided headache , fluctuating in intensity ( 39 in vas ) and accompanied by conjuntival injection and nasal congestion during exacerbation time .
with indomethacin 50  mg 3  times a day the hemicrania disappear , however , she developed disabling subjective tinnitus 1  month later .
we discontinued indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 18  month later .
a 64  years - old woman with 3  years history of right - sided headache , fluctuating in intensity ( 28 in vas ) .
with indomethacin 25  mg 3  times a day the hemicrania disappear , however , the patient suffer gastrointestinal disturbances .
we discontinued indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 10  month later .
a 76  years - old man with 6  month history of continuous left - sided headache and facial pain .
after 2  weeks on indometacina he complaint about pyrosis , that persists after omeprazol 40  mg per day .
we decided to discontinue indomethacin and introduced celecoxib 200  mg twice a day with completely recovery that persists 6  month later .
we present five patients suffering indomethacin - responsive headache case 1 suffering from paroxysmal hemicranias and cases from 2 to 5 from hemicranias continua ( table  1 ) .
all of them have absolutely response to indomethacin , but the presence of adverse reactions or intolerability let us discontinued and introduce celecoxib with completely recovery of the symptoms.table  1clinical characteristics of the patientscaseagegenderheadache typesidedoses ( mg)time in month142fhpleft20012256mhcleft40010378fhcleft40018464fhcright40010576mhcleft4006all doses correspond to celecoxibf female , m male , hc hemicrania continua , hp hemicrania paroxistica clinical characteristics of the patients all doses correspond to celecoxib f female , m male , hc hemicrania continua , hp hemicrania paroxistica indomethacin is consider the first - choice drug for the treatment of  indomethacin - responsive headaches  , and the headache resolution is consider as a diagnosis criteria in some of theses headaches .
although other drugs have been reported as useful treatment , most of them are anecdotic or single cases [ 915 ] .
other anti - inflammatory drugs that have been demonstrated as alternative drugs , in particular piroxicam , however , their efficacy is lower when compared with indomethacin .
the pathophysiology of theses  indomethacin - response headache  are still unknown , but the cyclo - oxygenase ( cox)-2 should be implicated in the pathogenesis .
celecoxib have been previously reported to be effective in the treatment of other indomethacin - responsive headache [ 311 ] , however , there was no absolutely response in all patients .
anyhow , in our experience celecoxib is a good option treatment for patients suffering from hemicrania continua or chronic paroxysmal hemicranea that presents indomethacin adverse effects .

Answer:
paroxysmal hemicrania and hemicrania continua are both indomethacin - responsive headaches .
 although indomethacin use to be well tolerated , some patients developed gastrointestinal side effects .
 we report four cases of hemicrania continua and a patient suffering chronic paroxysmal hemicrania completely responsive to celecoxib . in our experience celecoxib
 is a good option treatment for patients suffering from hemicrania continua or chronic paroxysmal hemicranea that presents indomethacin adverse effects .


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:
carbohydrates play critical roles during pollen growth and development , then in the final phase prior to dispersal carbohydrates change to prepare pollen for dispersal . following dispersal and during pollen storage , the various metabolites comprising the carbohydrate pool change in relative proportion , a behavior that is understood as an adaptation for sustaining pollen viability in time .
sucrose in particular may be of particular importance during pollen storage , as variations among species for pollen desiccation tolerance have been linked to sucrose content .
sucrose may replace water to preserve native protein structures and spacing between phospholipids in the plasma - membrane during dehydration .
the role of starch and sugars in pollen development , dispersal , and maintenance of viability has not been determined for any member of the cycadales , and is therefore a focus of needed research .
several authors have conducted robust surveys and noted that starchy pollen occurred disproportionately among anemophilous species .
representatives from the cycadales were absent from these surveys and this should be corrected , as cycad pollination studies have only recently illuminated the sophisticated pollination syndromes that characterize the threatened plant group . although arthropods were collected from reproductive structures on various cycad taxa in the past , the scientific community largely ignored their potential role as pollinators due to the established belief that all cycads were anemophilous .
the pendulum swung in the 1980s and 1990s when extensive experimental evidence confirmed mutualisms between cycad species and specialist insect pollinators .
more recently , ambophily has been confirmed or proposed for several cycas species where wind has been shown to augment insect pollination .
furthermore , variations in aggregation tendencies and settling velocity have been reported for pollen from various cycad species .
this is an opportune time to add members of the cycadales to studies that have linked the relationship of pollen carbohydrates to insect versus wind pollination strategies .
the insect pollinators of cycads gather on male cones , where the adults socialize , mate , and use the post - dispersal male strobilus tissue as larvae food ( fig .
the study of idioblasts within cycad sporophyll tissues has illuminated intricacies in how general tissue chemistry may interact with pollinator feeding behaviors .
for zamia furfuracea , these idioblasts remained intact in the male sporophyll tissue but appeared to release their contents into female sporophyll tissue prior to ovule receptivity .
the authors concluded that toxins remained sequestered within the idioblasts for male tissue only , such that the pollinators could feed on parenchyma tissue around the idioblasts or consume intact idioblasts which protected insect metabolism from the toxins after consumption .
many but not all cycad species studied in this context exhibited similar idioblast traits . for example , cycas rumphii and stangeria eriopus strobili did not contain identifiable idioblasts .
in contrast , macrozamia lucida and microcycas calocoma exhibited idioblast breakdown prior to pollination stage for both male and female sporophyll tissues .
the interactions among carbohydrates , nutrients , and toxins within cycad strobili tissues in relation to these idioblasts may prove to be of crucial importance for developing a full understanding of how pollinators feed on the plant 's reproductive tissues while enacting effectual pollination .
conservationists in need of improved knowledge of various pollination syndromes within the cycadales will require more studies within this context .

left : microstrobilus tissue is tunneled and consumed by larvae ( arrows ) immediately after pollen dispersal .
right : within days the entire microstrobilus is reduced to frass and pupation ( arrow ) heralds in a new generation of pollinators . the role of cycad sugars in mediating
left : microstrobilus tissue is tunneled and consumed by larvae ( arrows ) immediately after pollen dispersal .
right : within days the entire microstrobilus is reduced to frass and pupation ( arrow ) heralds in a new generation of pollinators . the role of cycad sugars in mediating
the majority of cycad pollinators consume strobilus tissue , but direct consumption of cycad pollen may occur for some cycad pollinators . cumulative research on pollen digestion
the addition of cycads to studies that determine carbohydrate and nutritional quality of pollen will greatly improve this line of research whether the mutualisms represent ancient associations that pre - dated angiosperms or examples where the contemporary mutualisms were recently derived from an initial antagonistic relationship .
the reproductive structures of cycad species exhibit thermogenesis and volatile emissions at the time of pollination , traits that mediate pollinator behavior and maintain pollinator specificity .
research is accumulating in areas such as modeling the plant behavior   and parsing the influence of specific volatiles on insect behavior . enacting synchronized thermogenesis and volatile biosynthesis
is an exceedingly expensive plant behavior , and no studies have determined the tissues of residence , quantities , and stoichiometric relations of the carbohydrate reserves that are mobilized to fund those activities .
droplets have been documented at the micropyle location on cycad ovules , and these droplets contain metabolites that may provide a reward for pollinators .
studies that marked pollinators then used deposition of the markers to track pollinator behavior have confirmed that the pollen they vector is trapped by the ovule droplets .
this remarkable female strobilus behavior represents a system that would be interesting to study in relation to specificity of pollinator attraction , diversity of sugar rewards , and cycad phylogeny .
droplets may exhibit taxon - specific carbohydrates that are suited to attracting and nourishing specific specialist pollinators .
our recent report of fructose , glucose , and sucrose content in cycad tissues sets the stage for designing continued research on how non - structural carbohydrates are involved in cycad pollination biology . moreover , cycad horticulturists routinely harvest , store , and ship pollen prior to its use for successful pollination .
improved understanding of how carbohydrates and other factors influence pollen viability and longevity would improve protocols for artificial pollination .
finally , the risks associated with coextinctions are very real during this phase of the anthropocene , and species with complex life history traits , such as cycads , appear to be at greater risk for direct involvement in coextinctions . an increase in knowledge of how cycad carbohydrates influence successful pollination relationships may help reduce the risks of coextinctions in these mutualisms that support contemporary cycad biology .

Answer:
cycad biology , ecology , and horticulture decisions are not supported by adequate research , and experiments in cycad physiology in particular have been deficient .
 our recent report on free sugar content in a range of cycad taxa and tissues sets the stage for developing continued carbohydrate research .
 growth and development of cycad pollen , mediation of the herbivory traits of specialist pollinators , and support of expensive strobilus behavioral traits are areas of cycad pollination biology that would benefit from a greater understanding of the role of carbohydrate relations .


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:
tophi can present as a first sign of hyperuricemia but literature has limited reports as far as flexor tendon contracture presenting as a first clinical sign of gout is concerned .
we report a case of tophaceous gout with finger flexion contracture as its first sign .
a 45 years old man presented in our out patient department with complaint of inability to extend middle finger of his left hand along with a mass growing over volar aspect of forearm for over few months . on physical examination a firm
hard mass around 2 * 2 cm was found over volar aspect of forearm just proximal to flexor retinaculam .
clinical suspicion of tb tenosynovitis , was kept as a first diagnosis followed by soft tissue neoplasm and subsequently surgical exploration was performed . a whitish chalky infiltration of tendon of fds , synovial adhesion of other tendons along with median nerve embedded within hypertrophied synovium of flexor tendon noted .
patient underwent synovectomy and excision of tendon of fds to middle finger following histo - pathological evaluation a diagnosis of tophaceous gout was made with serum uric acid level being 8.6 mg / dl .
a review of the literature reveals that gouty arthritis of the wrist is rare in isolation .
gout at the wrist as the initial appearance of the condition occurs between 0.8 to 2% of all gout cases .
gout occurs when serum uric acid levels are persistently higher than 6.8mg / dl . since tophaceous gout can be seen scarcely in well controlled hyper - uricaemic patient thus making preoperative diagnosis of intratendinous tophi even more strenuous .
tophi are chalky , gritty accumulations of monosodium urate crystals that build up in soft tissue of an untreated gouty joint .
the peak incidence of gout is between the ages of 3050 with the prevalence increasing with age .
tophi can present as a first sign of hyperuricemia but literature has limited reports as far as flexor tendon tophaceous infiltration presenting as a first clinical sign of gout is concerned [ 2 - 4 ] .
we report a rare case in which intratendinous tophaceous gout within the flexor digitorum superficialis ( fds ) tendon could not be differentiated from tubercular tenosynovitis or neoplasm preoperatively more so as it was seen in a patient with no prior history suggestive of hyperuricemia .
a 45 years old man presented in our out patient department with complaint of inability to extend middle finger of his left hand along with a mass growing over volar aspect of forearm for over 2 months [ fig 1 ] .
there was previous history of pain at wrist on finger movement which subsided gradually along with the decline in extension of middle finger .
there was no associated history of fever , loss of weight or appetite , night sweats , malaise or fatigue .
there was no history of trauma , pain in other joints of the body , morning stiffness of the back or hand joints , or continuous use of vibratory tools .
hard mass around 2 * 2 cm was found over volar aspect of forearm just proximal to flexor retinaculam .
it was non tender , non compressible , mobile at right angle to anatomical axis of forearm .
movement at wrist was normal with restriction of movement of middle finger in sagittal plane .
laboratory findings showed all within normal limits except serum uric acid which was 8.6 mg / dl .
magnetic resonance imaging ( mri ) showed that the mass was within the fds which on axial t1 [ fig 2 ] appeared as heterogenous isointense lesion while on coronal t2 stir [ fig 3 ] showed heterogenous mixed hypointense  hyperintense lesion .
clinical suspicion of tubercular tenosynovitis , soft tissue neoplasm and tophaceous gout was made and subsequently surgical exploration was performed .
an incision along the flexor crease , extending further proximally while maintaining the longitudinal orientation taken . on longitudinal slit of thickened tendon sheath chalky white liquid emanated .
on futher exploration there was whitish chalky infiltration of tendon of fds [ fig 4 ] , synovial adhesion of other tendons along with median nerve embedded within hypertrophied synovium of flexor tendons . since the mass was noted well proximal to flexor retinaculam that probably could be the reason for flexor contracture and sparing of median nerve .
patient underwent synovectomy and tenotomy of fds to middle finger because of heavy intratendinous infiltration of the tophus along with destruction of the tendinous tissue .
histopathological evaluation of the chalky white substance showed fibroconnective tissue showing hyalinized areas with evidence of saponification surrounded by palisades of foreign body type giant cells and chronic inflammatory cells .
the postoperative course was uneventful with no remarkable functional deficit from the removal of the superficialis endon to the middle finger [ fig 6 ] .
gout at the wrist as the initial appearance of the condition occurs between 0.8 to 2% of all gout cases .
gout patients who are not treated have a 1930% chance of developing gout in the wrist during their lifetime .
these nodules may not be recognized as tophi because the clinical diagnosis of gout in many instances is not straightforward . in the past reports ,
all intratendinous infiltrations of tophaceous gout occurred at the wrist and existed with carpal tunnel syndrome .
we present an uncommon and unusual case of gout in the flexor tendon of forearm which occurred in isolation in a patient with no prior medical history of the recorded disease .
measurement of serum uric acid level in chronic tophaceous gout may or may not be conclusive of hyperuricemia as some patients with diabetes or even alcoholics can have normal to lower levels   although fnac prior to definitive intervention would have helped us to achieve the diagnosis preoperatively but rather we had gone for definitive intervention but in no way over riding the role of fnac as the procedure of choice to achieve definitive diagnosis [ 8 ] .
surgical intervention like tenotomy or tenosynovectomy are required to debulk tophaceous deposits , improve smooth gliding of tendon and decompress nerves but primarily medical management to treat gout remains the gold standard .
short - term outcomes are consistently good   but the risk of rupture [ 11 ] or recurrency remain if medical control is not achieved .
a review of the literature reveals that gouty arthritis of the wrist is rare in isolation .
gout at the wrist as the initial appearance of the condition occurs between 0.8 to 2% of all gout cases .
gout occurs when serum uric acid levels are persistently higher than 6.8mg / dl . since tophaceous gout can be seen scarcely in well controlled hyper - uricaemic patient thus making preoperative diagnosis of intratendinous tophi even more strenuous . in indian subcontinent tubercular tenosynovitis

Answer:
introduction : tophi can present as a first sign of hyperuricemia but literature has limited reports as far as flexor tendon contracture presenting as a first clinical sign of gout is concerned .
 we report a case of tophaceous gout with finger flexion contracture as its first sign.case report : a 45 years old man presented in our out patient department with complaint of inability to extend middle finger of his left hand along with a mass growing over volar aspect of forearm for over few months . on physical examination a firm
 hard mass around 2 * 2 cm was found over volar aspect of forearm just proximal to flexor retinaculam .
 mri showed mass within tendon of fds .
 clinical suspicion of tb tenosynovitis , was kept as a first diagnosis followed by soft tissue neoplasm and subsequently surgical exploration was performed . a whitish chalky infiltration of tendon of fds , synovial adhesion of other tendons along with median nerve embedded within hypertrophied synovium of flexor tendon noted .
 patient underwent synovectomy and excision of tendon of fds to middle finger following histo - pathological evaluation a diagnosis of tophaceous gout was made with serum uric acid level being 8.6 mg / dl.conclusion : a review of the literature reveals that gouty arthritis of the wrist is rare in isolation .
 gout at the wrist as the initial appearance of the condition occurs between 0.8 to 2% of all gout cases .
 gout occurs when serum uric acid levels are persistently higher than 6.8mg / dl . since tophaceous gout can be seen scarcely in well controlled hyper - uricaemic patient thus making preoperative diagnosis of intratendinous tophi even more strenuous .


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:
Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core

Paper sections:

While M4 positive allosteric modulators (PAMs) hold great therapeutic promise for schizophrenia1–4 and a number of other CNS disorders,5,6 a lack of translatable chemotypes (and very limited structural diversity within known chemotypes) has hampered the field from realizing the true therapeutic potential of selective M4 activation. The area has been dominated by differentially functionalized 3-amino–thieno[2,3-b]pyridine cores, typified by 1, or 5-amino-3,4-dimethylthieno[2,3-c]pyridazine such as 2 (Figure 1).7–16 Multiple HTS campaigns revealed similar chemotypes, with the exception of 3 and 4;17,18 however, these also failed to progress to development candidates. However, 4 (based on a 5,6-dimethyl-4-(piperidin-1-yl)thieo[2,3-d]pyrimidine core) was optimized to 5, which demonstrated exceptional CNS penetration.18 With the goal of arriving at a development candidate, we recently reported on a scaffold hopping exercise that afforded 6.19 In this Letter, we will discuss the synthesis, SAR and DMPK profiles of M4 PAMs based on a novel 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which demonstrated robust SAR beyond that of related 4–6, and holds promise for translation.

Recently, we performed a new functional M4 high-throughput screen (HTS) in 1536-well assay format against the ~100,000 compound Vanderbilt collection. Of the four structurally novel M4 PAMs that were identified, VU0619856 (7) represented an exciting new chemotype for the M4 field, and while related to 4 and 5, M4 PAM potency peaked at ~600 nM in these earlier series.18 New M4 PAM 7 was active on both rat and human (EC50s of 2565 nM and 897 nM respectively) with promising points of diversity. The initial strategy was to utilize an iterative parallel synthesis to explore the amide portion of the molecule followed by evaluation of the 3-cyano quinoline core. Would the 3-cyano quinoline be a quinazoline mimetic as in 5, or would SAR diverge?

The synthesis of analogs of M4 PAM 7, congeners 11 (secondary amides) and 12 (tertiary amides), was straightforward (Scheme 1), and employed a diverse collection of amines (benzyl, aryl/heteroaryl amines and secondary amines). Starting from commercial 4-chloro-6-fluoroquinoline-3-carbonitrile 8, an SNAr with ethyl piperidine-4-carboxylate provided 9 in 98% yield. After hydrolysis under basic conditions to provide the acid 10, a library of amides 11 and 12 were generated under standard HATU conditions.

While subtle improvement in potency was observed with a variety of substituted benzyl amines (11b–d), compounds such as 11d had high predicted hepatic clearance, CLhep (h = 19, r = 61), and low brain distribution in rat (brain:plasma Kp = 0.29, Kp,uu = 0.26). The aniline 11e, substituted with a primary sulfonamide, showed very promising hM4 potency (248 nM, 6% ACh), but later was determined to be a P-gp substrate (MDCK-MDR1 ER = 83). Analog 11g proved to be the most potent secondary amide in the series, with an hM4 PAM potency of 147 nM; however, its DMPK profile was lacking. Importantly, this new chemotype already surpassed the PAM potency floor of 4 and 5 (hM4 PAM EC50s ~ 600 nM).

As disposition and CNS penetration were low with the secondary amides, we profiled tertiary amides to assess the impact of removing one hydrogen-bond donor. As shown in Table 2, representative tertiary amide analogs 12 suffered a diminution in hM4 PAM potency relative to secondary amides 11. However, we still advanced 12d, a 648 nM M4 PAM into in vitro and in vivo DMPK profiling. PAM 12d, like analogs 11, displayed high predicted hepatic clearance, CLhep (h = 20, r = 64), but removal of the secondary amide H-bond donor improved CNS penetration (rat brain:plasma Kp = 1.3, Kp,uu = 0.68). These data led us to generate chimeras between the new 3-cyano quinoline core and the piperidinyl ethers of 5 and explore if this structural change would bring balance to hM4 PAM potency while maintaining favorable CNS penetration.

Synthesis of the targeted chimera ligands 14 was facile (Scheme 2). Once again, commercial 4-chloro-6-fluoroquinoline-3-carbonitrile 8 underwent an SNAr reaction with 4-hydroxypiperdine to provide 13 in 90% yield. Then, a Mitsunobu reaction with various functionalized phenols and heteroaryl alcohols delivered analogs 14 in yields ranging from 10–80%.

As shown in Table 3, these chimeric ligands proved to possess hM4 PAM activity, but SAR was steep with few active PAMs. Of these, 14f (VU6009003) stood out as a potent hM4 PAM (EC50 = 197 nM, pEC50 = 6.78 ± 0.17, ACh Max = 79± 10). Prior to deeper characterization of 14f, we elected to survey the necessity of the 3-cyano quinolone core, and assess if deletion of the 3-CN moiety, or additional functionalization of the quinoline core would afford hM4 PAMs for further evaluation. To assess this possibility, analogs 17 were readily prepared in two steps from commercial 15 and 5-fluoro-2-methlypyridine via an SNAr reaction to provide, after Boc deprotection 16. A second SNAr reaction with various 4-halo quinolines produced analogs 17.

Deletion of the 3-CN moiety as in 17a led to a greater than 10-fold loss in hM4 PAM potency, highlighting the necessity of this novel moiety. Moreover, this result suggests that the 3-CN moiety in this core is not bioequivalent to the nitrogen of the quinazoline-based hM4 PAMs represented by 5. Replacement of the 6-fluoro moiety with either a 6-Cl atom (17b, hM4 PAM EC50 = 905 nM) results in a ~4-fold loss of potency, while replacement with a methyl group (17c, hM4 PAM EC50 = 3018 nM) results in a ~15-fold loss in hM4 PAM potency relative to 14f. Of these analogs 17, only a 6,8-difluorocongener 17e, proved of equivalent potency to 14f.

Thus, 14f (VU6009003) emerged from this effort as a novel M4 PAM worthy of further profiling. PAM 14f was potent at both human M4 (197 nM, 80% ACh Max) and rat M4 (437 nM, 74% ACh Max) with very modest species difference in PAM potency, and a marked improvement over the HTS hit 7. In terms of physicochemical properties, 14f was a low molecular weight compound (MW =362) with an attractive xLogP (2.83) for a CNS agent (Table 5). In a microsomal intrinsic clearance assay, 14f displayed moderate clearance in both species (predicted human CLhep = 15 mL/min/kg, predicted rat CLhep = 52 mL/min/kg) with moderate fraction unbound in human plasma (fu = 0.024), rat plasma (fu = 0.031) and rat brain (fu = 0.014). In our standard rat plasma:brain level IV cassette paradigm, 14f showed excellent CNS penetration with a rat brain:plasma partitioning coefficient (Kp) of 5.3, and when corrected for fraction unbound in plasma and brain, a Kp,uu of 2.4. We also assessed human P-gp efflux potential in a MDCK-MDR1 transwell assay, and found no P-gp liability (ER = 1.1) coupled with high passive permeability (Papp = 28 × 10−6 cm/s). In vivo, 14f displayed lower clearance (CLp =36 mL/min/kg) in rat (IV PK cassette, 0.2 mg/kg) than predicted (CLhep = 52 mL/min/kg), with a short t1/2 (1.7 hours) and moderate volume (Vss = 3.2 L/kg). In a dog IV PK cassette study (0.2 mg/kg), 14f displayed clearance (CLp = 41 mL/min/kg) at hepatic blood flow with a t1/2 of 1.6 hours (likely as a consequence of moderate-to-high volume, Vss = 4.0 L/kg); however, 14f did display a reasonable IVIVC with predicted hepatic clearance in dog (CLhep = 27 mL/min/kg) and good fraction unbound (fu = 0.045). While attractive overall in terms of novel chemotype, favorable CNS MPO score (>5),21 fraction unbound and CNS penetration, the disposition of 14f remains to be addressed (after a deeper understanding of metabolic soft spots).

In summary, an HTS campaign identified a new M4 PAM chemotype 7, related to 4 and 5, but displaying distinct SAR, improved M4 PAM functional potency and enhanced CNS penetration. The discovery of new M4 PAM chemical matter is of critical importance to enable translation to the clinic, as the field has been largely dominated by limited chemotypes 1 and 2, fraught with development challenges. Metabolite identification studies and further optimization efforts are underway and will be reported in due course.

Answer: This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp = 5.3, Kp,uu = 2.4; MDCK-MDR1 (P-gp) ER = 1.1).


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:
multiple carcinoid tumors of the small intestine are rare and are very difficult to detect preoperatively .
a 75-year - old woman in whom the bleeding focus could not be found by upper and lower endoscopy and abdominal ct was admitted for evaluation of anemia .
we examined the patient with total double - balloon endoscopy ( dbe ) and located multiple submucosal tumors .
we report a case of a successful laparoscopic operation for multiple carcinoid tumors in the small intestine without intraoperative endoscopy . total digestive tract observation using dbe
tumors of the small intestine account for 1% to 2% of all gastrointestinal neoplasms ( only 0.3% of all neoplasms ) .
however , the incidence of small intestine cancer has increased dramatically over the past 30 years , and the increase in carcinoid tumors has been largely responsible .
carcinoids of the ileum account for 15.4% of all gastrointestinal carcinoids   and are multicentric in 2030% of patients .
the lack of signs and symptoms , lack of definitive preoperative diagnostic tests , and the variable efficacy of available tests make small intestine tumors difficult to diagnose .
the recent development of capsule endoscopy ( ce ) and double balloon endoscopy ( dbe ) has improved diagnostic capabilities for the small intestine .
we report the first case of multiple carcinoid tumors of the small intestine preoperatively diagnosed by dbe and treated with laparoscopic surgery .
a 75-year - old woman was referred to our hospital with melena and severe anemia ( hemoglobin ( hb ) 7.2 g / dl ) . she had a history of stroke at age 59 years , and was being treated with antiplatelet therapy at the time of admission to the referring hospital . at that hospital ,
the source of gi bleeding was not revealed by upper and lower gastrointestinal endoscopy examination , abdominal computed tomography ( ct ) , or ultrasound ( us ) . through radiological enteroclysis ,
an elevated lesion was found in the ileum , which was suspected to be a submucosal tumor and measured 15 mm in diameter .
after 2 months at the referring hospital , she was admitted to our hospital for a thorough investigation of the small intestine .
physical examination revealed her abdomen to be soft and flat without any pain or tenderness .
results of blood tests were as follows : hb 11.3 g / dl ( normal : 11.115.2 g / dl ) , red blood cell count 418 10/ml ( normal : 380540 10/ml ) , and hematocrit 35.3% ( normal : 35.645.4% ) .
we then examined the patient with peroral dbe ( en-450p5 : fujifilm medical co. , ltd . ,
a tumor was located about 250 cm from the ligament of treitz and measured 8 mm in diameter ( figure 1 ) .
histologic examination of the biopsy sample obtained by endoscopy confirmed the diagnosis of a carcinoid tumor .
the tumor was composed of small uniform epithelial cells , which stained positively for chromogranin a and synaptophysin .
another tumor detected through peranal dbe was located about 110 cm from the ileocecal valve and measured 15 mm in diameter .
also , other small tumors were detected that measured 3 mm and 5 mm in diameter and had a relatively smooth surface , similar to a submucosal tumor .
these small tumors were diagnosed as carcinoid tumors by endoscopic findings , whereas histologic examination could not make this diagnosis . the largest tumor had ulcerations , which could account for the gi bleeding ( figure 2 ) .
the patient underwent partial resection of the small intestine by laparoscopic surgery ( resected portion : 23.8 cm ) .
she had already undergone a preoperative total small intestinal examination using dbe ; therefore , it was not necessary to perform intraoperative endoscopy .
the resected specimen contained tumors measuring 1410 mm , with central ulceration ( figure 3 ) , 2.86 mm and a tumor 3 mm in diameter .
microscopically , the tumors were composed of small uniform epithelial cells ( figure 4b ) , which stained positively for chromogranin a and synaptophysin ( figure 5 ) .
no metastases were found in the regional lymph nodes , and the surgical margins were negative for tumor cells .
follow - up dbe was performed 18 months later , and there was no sign of recurrence in the small intestine .
this is the first report of laparoscopic surgery without the use of intraoperative endoscopy for multiple carcinoid tumors of the small intestine , which was possible because the tumors were diagnosed before surgery by dbe .
carcinoid is the second most common malignancy , accounting for approximately 2025% of all small intestine lesions .
carcinoid tumors are more common in the ileum ( most within 60 cm of the ileocecal valve ) than in the jejunum or duodenum , and lesions may be multiple and/or metastatic ( liver and lungs ) at the time of diagnosis because one fourth of carcinoid tumors in the small intestine are multiple . on the guideline , by far the majority of small intestinal neuroendocrine tumors ( nets , including carcinoid ) are malignant in nature . whether liver metastases are present or not , resection of the primary tumor is appropriate to cure or to delay progression that would otherwise endanger the small bowel .
carcinoids of the rectum , stomach , and duodenum generally are found by endoscopy at an early stage , whereas carcinoid tumors of the small intestine usually are discovered after resection of the small intestine for symptoms of obstruction or during exploration of the small intestine in search of a primary tumor after distant metastases have been found [ 2,912 ] . through conventional imaging techniques ( e.g. ,
ct , us , double contrast barium study ) , few tumors of a small diameter are identified .
currently , with advancement in methods of ce , small intestine tumors can be located .
ce had a high diagnostic yield of 45% for identification of primary small intestinal carcinoid tumors .
however , it remains purely a diagnostic procedure at present because it is not suitable for histological diagnosis and procedures .
for this reason , if laparoscopic surgery is performed in a patient who was diagnosed as having multiple carcinoid tumors of the small intestine , it is usually necessary to perform intraoperative endoscopy to confirm that the lesion is a carcinoid tumor .
it is notable that in reporting the results of their study , m. bellutti et al .
suggested that intraoperative endoscopy is a potential gold standard for nets . on the other hand
a submucosal tumor of the ileum or the jejunum was detected by dbe in 7 of 12 patients ( 58% ) with suspected carcinoid syndrome .
in addition , tumor marking using injection of ink for the exact location during dbe has been helpful for subsequent operations , especially for laparoscopic resection . by utilizing dbe
, we were able to locate the multiple ileal tumors and to perform laparoscopic surgery without intraoperative endoscopy in the patient reported here .
dbe is a safe procedure , with low complication rates even when therapeutic maneuvers are performed .
as only dbe allows direct , controlled visualization of small intestine tumors and their histological confirmation preoperatively , it may be considered the gold standard for the diagnosis of such tumors .
dbe is extremely useful to detect and diagnose asymptomatic small lesions in the small intestine .
based on the case presented here , we recommend total digestive tract observation using dbe before performing laparoscopic operation for multiple tumors of the small intestine .

Answer:
summarybackgroundmultiple carcinoid tumors of the small intestine are rare and are very difficult to detect preoperatively.case reporta 75-year - old woman in whom the bleeding focus could not be found by upper and lower endoscopy and abdominal ct was admitted for evaluation of anemia .
 we examined the patient with total double - balloon endoscopy ( dbe ) and located multiple submucosal tumors .
 the multiple carcinoid tumors were resected successfully under laparoscopy.conclusionswe report a case of a successful laparoscopic operation for multiple carcinoid tumors in the small intestine without intraoperative endoscopy .
 total digestive tract observation using dbe is very useful for laparoscopic operation for multiple tumors in the small intestine .


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:
however , cost , difficulty of implementation , and other barriers impede adoption of such systems , and studies have documented low rates of technology acquisition and implementation in emergency department ( ed ) and other settings .
a study of residency - affiliated eds in 2000 found low rates of adoption , with only 7% reporting fully implemented technology for medication error checking , 18% for computerized medication order entry , and 21% for clinical documentation .
a 2006 survey of health information technology in all massachusetts eds found similar results , with 11% of respondents reporting fully implemented technology for medication error checking .
another national study showed that , during 20012003 , only 31% of us eds used electronic medical records in any form .
our hypothesis is that fewer than half of us eds had adopted electronic health records systems and related decision - support tools by 20052006 .
we report on data collected as part of the national ed safety study ( nedss ) .
we recruited eds mainly by inviting network members . since most members are affiliated with an emergency medicine residency program ( i.e. , are academic eds ) , we also recruited non - academic and other eds not affiliated with emnet through postings on emergency medicine list servers , by contacting sites directly , and through presentations at emergency medicine meetings .
for the parent national ed safety study , each site had a site responsible investigator .
the survey asked about ed attributes and adoption of the health information technology applications shown in table  1 .
these applications were chosen by the authors as representative of the diverse applications available today , within the constraints of a larger survey with other goals .
we performed all calculations with sas 9.12 ( sas institute , cary , nc ) .
table  1characteristics of 68 emergency departments surveyedcharacteristicn ( % ) median computerization scoreemergency medicine residency affiliation  yes51 ( 75%)9  no17 ( 25%)8annual census ( visit per year )  < 10,0000n / a  10,00019,9990n / a  20,00029,9991 ( 1%)5  30,00039,99912 ( 18%)8.5  40,00049,99912 ( 18%)7.5  50,00043 ( 63%)9us region  northeast30 ( 44%)8  midwest15 ( 22%)9  south10 ( 15%)9  west13 ( 19%)8we surveyed key informants at 69 us eds , as part of the national emergency department safety study , with 68 ( 99% ) of eds surveyed respondingthe computerization score was simply a way for us to count the number of information technologies that had been acquired .
we calculated the score by assigning one point for each acquired application listed in table  2 characteristics of 68 emergency departments surveyed we surveyed key informants at 69 us eds , as part of the national emergency department safety study , with 68 ( 99% ) of eds surveyed responding the computerization score was simply a way for us to count the number of information technologies that had been acquired .
we calculated the score by assigning one point for each acquired application listed in table  2 our main outcome measure is descriptive : how many eds have adopted which applications ?
our secondary objective was to determine whether ed characteristics predicted adoption of health information technology .
firstly , we selected one application that seemed to represent the potential of information technology to improve health care .
there is substantial debate about what constitutes  meaningful use  of information technology , and we felt that selecting one crucial application for analysis would be the best way to compare across eds . for the purpose of this analysis , we selected computerized medication ordering as the application .
we chose this application because medication ordering represents a crucial site of potential intervention to improve adherence to recommended care and avoid error .
we studied this as an outcome variable by creating a logistic regression model with computerized medication order entry as the dependent variable .
we categorized eds according to emergency medicine residency affiliation ( binary ) , annual census ( continuous ) , and region ( categorical : northeast , midwest , south , and west ) .
we used multiple logistic regression to model these characteristics as predictors of adoption of computerized medication ordering .
we used the hosmer - lemeshow goodness of fit test to evaluate for non - linearity .
secondly , we did not wish to limit our investigation to any one application or combination of applications , as was done in the analysis described above .
thus , we also compared eds by the raw number of applications they had adopted .
we accomplished this by creating a computerization score , as was done in a prior study .
this score is simply a count of applications , with one point assigned for each acquired application .
we then used multiple linear regression to predict computerization score by the above ed characteristics and planned to consider any characteristic to be a
significant  predictor of the computerization score if the p - value of its beta coefficient was  0.05 . we used the sas spec option to assess for heteroscedasticity and inspected residual plots for qualitative evidence of a relationship .
of 69 eds surveyed , 68 ( 99% ) in 23 us states completed the survey .
the participants were generally large urban academic eds , with 44% located in the northeast .
table  2 shows the number and proportion of eds reporting availability of selected health information technologies .
computerized physician order entry , clinical decision support , and bar coding technology were present in fewer than 40% of eds .
in contrast , some other applications were present in most of the eds surveyed , including laboratory test ordering and results , notes from prior encounters , and ecg results .
the right - hand column of table  1 shows the computerization score ( see methods ) , stratified by ed characteristics .

table  2information technology in 68 us emergency departmentsinformation technology applicationnumber ( % ) of eds reporting availability of each applicationcomputerized physician medication order entry26 ( 38%)clinical decision support for medication allergies13 ( 19%)clinical decision support for drug - drug interactions9 ( 13%)outpatient notes39 ( 57%)inpatient notes43 ( 63%)surgical notes53 ( 78%)prior ed visit notes54 ( 79%)laboratory results66 ( 97%)laboratory test ordering39 ( 57%)test ordering other than laboratory tests42 ( 62%)radiology results67 ( 99%)ekg results62 ( 92%)patient tracking50 ( 74%)bar coding for patient , medication , or sample identification14 ( 20% ) information technology in 68 us emergency departments our analysis of ed characteristics did not reveal any significant variation in availability of electronic medication ordering or computerization score , by emergency medicine residency affiliation , annual census , or region .
businesses from restaurants to banks and airlines rely on such technology to process information that has much in common with medical information .
why , then , would our nationwide sample of eds reveal that only 19% have the capability to check a medication order to see if the patient has a documented allergy to that medication ?
reasons might include apprehension . in the enthusiasm to promulgate the spread of health information technology , the downsides are often under - emphasized .
the present report echoes the findings of the three prior studies of health information technology adoption in us eds
only two of these prior studies assessed the adoption of individual applications , such as computerized physician order entry .
one was a survey of us emergency medicine residency - affiliated eds in 2000 , and the second was a survey of all massachusetts eds in 2006 .
our ability to conduct direct quantitative comparisons across time is limited , because different eds participated in the surveys .
all three studies revealed that a minority of eds had computerized medication ordering : 38% in the present national study , 15% in the 2006 ma study , and 18% in the 2000 national study .
quantitatively , the increase from 18% to 38% might indicate wider dissemination of these technologies , or might be due to sampling variation .
qualitatively , it seems reasonable to conclude from these three studies that most us eds do not have electronic medication ordering , or its companion technology , medication error checking .
however , this conclusion must be caveated by the fact that large academic eds were over - represented in these samples .
studies of health information technology adoption in physicians offices and hospitals throughout the country also revealed slow uptake by 2008 [ 8 , 9 ] .
these studies found that only 7.6% of us hospitals have a basic electronic records system , and 1.5% a comprehensive one .
( these studies defined  basic  as including only demographic information , cpoe , laboratory and imaging results , and  comprehensive  as including the above , plus clinical notes , plus electronic prescribing , radiographic image display , and decision support . )
only 4% of physicians offices have a fully functional electronic - records system , and 13% have a basic system .
ed - based studies also show that some health information technology applications are widespread , including patient tracking ; ordering tests ; and displaying prior visit notes , ecgs , and laboratory and radiology results [ 2 , 3 , 5 ] .
an analysis of the types of health information technology may improve our understanding of these results .
one type of application is computationally simple , merely entering and extracting information from a database , and displaying it .
the other type of application requires all of the above processes , plus algorithmic processing that seeks to supplement human cognition with computation . for lack of better terms
, we might refer to these two types of application as  passive  and  active  applications , respectively . from a workflow standpoint ,
such technologies include patient tracking ; ordering tests ; and displaying prior visit notes , ecgs , laboratory and radiology results .
active applications add functions designed to improve outcomes by reducing error or increasing adherence to the standard of care  they seek to change human behavior .
these applications often embody fundamental changes in clinical processes , and implementation is intertwined with changes in workflow [ 6 , 10 ] .
examples include computerized provider order entry and related error - checking functions , and decision support systems . in light of this dichotomization
, we can see that the present and prior studies reveal a high rate of adoption of passive applications in us eds and a low rate of adoption of active applications [ 2 , 3 ] .
( we included laboratory test ordering in the  passive  category for historical reasons .
such systems have been present in most eds for many years   and were not originally subject to behavior - modification technology . ) an optimistic interpretation of our data would be to celebrate the fact that most us eds did not invest in expensive , cumbersome , and even potentially risky systems prematurely . now that a large number of commercial and home - grown systems are available , we should take the time to study them and reach consensus on which would be best for particular environments .
we should pay particular attention to the interaction of information systems with human workflows [ 6 , 10 ] .
the certification commission for healthcare information technology formed an ed work group in 2007 , which is in the process of certifying various health information technology platforms for ed use , in concert with the health level seven project .
this type of certification process may be an important first step in improving the types of systems that are available , or at least our understanding of what is available .
participating sites were generally large , urban , academic eds . because the underlying patient safety study focused on adult illnesses , the study excluded children s hospitals .
we did assess for variability in technology adoption by ed characteristics , and found no significant variation .
this improves our confidence in the generalizability of our data to other eds in the us , though , again , large academic eds were over - represented in the sample .
perhaps more saliently , the present results are similar to those of prior studies , from academic eds throughout the us , and all eds in massachusetts .
it remains true that we have little data on health information technology adoption in the 1/3 of us eds with an annual visit volume < 10,000 .
from the perspective of the individual patient , small eds have the same clinical goals as large eds .
but from a systems perspective , the marginal cost of health information technology in low - volume settings will be high relative to benefit , both financially and in terms of workflow modification and associated risks .
another limitation is the fact that our assessment was part of a larger survey , and thus , we could not conduct as detailed an inquiry as would have been desirable . in particular , we did not ascertain adoption of health information technology for medication order checking or decision support .
however , the low rate of adoption of medication order entry technology allows us to conclude with confidence that these technologies were not available in the majority of respondent eds .
active applications involve intertwining of technology and human workflows , and are intended to change behavior .
together with the findings of other studies , our results demonstrate that most us eds have adopted passive applications but not active applications that have been recommended forcefully [ 2 , 3 ] .
we view this as an opportunity , because careful analysis of available platforms and the pitfalls in their implementation may result in better outcomes and less difficulty in the implementation process .
the ideal forum for such analysis remains unclear , though the certification commission for healthcare information technology ed work group is a notable effort .

Answer:
backgroundinformation technology may improve patient safety , and is a focus of health care reform .
 a minority of emergency departments ( eds ) in massachusetts , and in academic eds throughout the us , have electronic health records.aimsassess health information technology adoption in a nationwide sample of eds.methodswe surveyed 69 us eds , asking site investigators about the availability of health information technology in 20052006 . using multiple linear regression , we compared adoption of technology by ed type ( emergency medicine residency affiliation , annual census , us region ) to assess generalizability of the findings.resultssixty-eight eds ( 99% ) provided information about health information technology ; 75% were affiliated with an emergency medicine residency , and all were urban .
 most respondents had applications that simply relay information from one place to another , including patient tracking ( 74% ) ; ordering tests ( laboratory 57% , others 62% ) ; and displaying prior visit notes ( 79% ) , ecgs ( 92% ) , laboratory ( 97% ) , and radiology ( 99% ) results .
 a minority had more - advanced applications , which seek to modify human behavior , including medication ordering ( 38% ) , allergy warnings ( 19% ) , and medication cross - reaction warnings ( 13% ) , and a few used bar coding ( 20% ) .
 there were no significant differences in technology adoption by ed type.conclusionsthis and prior studies suggest that some applications  particularly those relevant to modifying clinician behavior  are not widespread in us eds , while others are .
 the reasons for this are unknown , but might include expense and unintended consequences .
 the fact that the emergency medicine community has not rushed to adopt certain applications presents challenges and opportunities .


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 lingual tonsils develop at 6.5 weeks between the second and third arches ventrally while palatine tonsils develop at 8 weeks from second pouch ( ventral and dorsal ) .
tonsils are predominantly b - organs and b - lymphocytes comprise 5060% of tonsillar lymphocytes .
ample evidence shows that tonsils are involved in inducing secretory immunoglobulin production [ 4 , 5 ] .
both adenoids and tonsils are favourably located to mediate immunologic protection of the upper aerodigestive tract as they are exposed to air borne antigens .
tonsils are particularly designed for direct transport of foreign material from the exterior to the lymphoid cells .
involution of the tonsils begins after puberty , resulting in a decrease of the b cell population and a relative increase in the ratio of t to b cells .
the commonest indication for tonsillectomy is recurrent tonsillitis , which results in shedding the immunologically active cells and decreasing antigen transport function with subsequent replacement by stratified squamous epithelium [ 6 , 7 ] .
we investigated the common pathogens causing this condition in our hospital and report here our findings .
patients presenting at our clinic with signs and symptoms of chronic tonsillitis were enrolled for the study .
the study was explained to them and where children were involved , to their parents .
before the operation began , the laboratory was informed and a technician stood by to collect the tonsil as soon as it was removed .
sterile wide - mouthed container was provided and the excised tonsils were aseptically put into them and carried immediately to the laboratory for processing .
as soon as the tonsil reaches the laboratory , it is cut into two with a sterile surgical blade ; the inner surfaces were swabbed with sterile cotton swab , and inoculated onto two blood agar plates , one macconkey agar and one chocolate agar plate .
one blood agar plate was incubated anaerobically , the chocolate plate in 510% co2 while the rest of the plates were incubated aerobically .
the aerobic plates and the co2 plate were examined after 24 hours ; if no growth , they were reincubated for a further 24 hours after which if still no growth , they were discarded as negative .
the anaerobic cultures were examined at 72 hours and if no growth they were reincubated for a total of 7 days .
there were 34 bacterial isolates from 52 patients , giving a percentage positivity of 65.38% .
thirty isolates were gram - positive bacteria and only four were gram - negative , made up of two genera , klebsiella and pseudomonas .
staphylococcus aureus was the predominant isolate ( 15/34 , 44.1% ) , followed by group b streptococcus ( 12/34 , 35.3% ) .
others were , streptococcus pyogenes ( group a streptococcus ) , 1/34 , 2.94% ; and untypable streptococcus spp . 2/34 , 5.88% .
the gram - negative bacteria consist of klebsiella pneumoniae 3/34 , 8.82% and pseudomonas aeruginosa 1/34 , 2.94% ( table 1 ) .
there were no growths in 7 patients while 11 yielded growth of normal flora only .
all the cases were chronic and most of them took antibiotics before presenting to us .
the ratio of anaerobic to aerobic bacteria in saliva is approximately 10  :  1 because of variations in oxygen concentration throughout the oral cavity . invargsson et al . revealed that streptococcus pneumoniae was recovered in 19% of healthy children , hemophilus influenzae in 13% , group a streptococcus in 5% , and moraxella ( branhamella ) catarrhalis in 36% .
the frequency of pathogens decreases with age , possibly because of increased immunity . because the oropharynx is colonized by many organisms , most infections of wadeyer 's ring are polymicrobial . in our study ,
but in contrast with other researchers who found beta - hemolytic streptococci to be the predominant isolate [ 14 , 15 ] .
these authors also found that streptococcus pyogenes was isolated more frequently in recurrent tonsillitis while in the tonsillar hypertrophy , streptococci beta - hemolytic non a group predominated .
it has been suggested that fine - needle aspiration can be used in identifying tonsil core bacteriology in clinical settings .
methicillin resistant staphylococcus aureus ( mrsa ) , has been isolated from the surface and core tonsils in children .
we did not encounter any mrsa in our study ; and all the staphylococcus aureus isolated were sensitive to augmentin and vancomycin .
it would appear from our results , that augmentin should be our drug of choice in future treatment of tonsillitis from this centre .
the findings of kuhn et al . supported the etiologic role of hemophilus influenzae and staphylococcus aureus in hypertrophic tonsils with or without inflammation [ 18 , 19 ] .

Answer:
objectives . tonsillitis is a common infection in all age groups , especially under the age of five . organisms causing this condition vary from place to place .
 our aim is to find out the main causative agents of this condition in our hospital .
 patients and methods .
 fifty - two consenting patients who needed tonsillectomy in khamis civil hospital , kingdom of saudi arabia , between september 2006 and april 2007 , were enrolled for the study .
 swabs were taken from their inner surfaces and cultured for anaerobes and aerobes according to standard microbiological techniques .
 results .
 fifty - two patients , consisting of 30 males and 22 females were enrolled .
 their mean age was 9.81  6.47 .
 nearly 65% of patients had positive cultures while 35% were negative .
 the commonest bacteria isolated were staphylococcus aureus ( 44.1% ) ; and group b streptococcus ( 35.3 % ) .
 two gram - negative bacteria , klebsiella pneumoniae , ( 8.82% ) , and pseudomonas aeruginosa ( 2.94 % ) , were also isolated .
 no anaerobe was isolated .
 conclusion .
 gram - positive cocci , consisting of staphylococcus aureus and group b streptococcus ( streptococcus agalactiae ) , are the major causes of tonsillitis requiring surgery in our hospital .
 antibiotic treatment of this condition should be directed largely against these organisms .