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:
colonic necrosis has been described as a rare complication after the administration of kayexalate [ 1 , 2 ] . in this case study , we present a case of calcium polystyrene sulfonate - induced colonic necrosis and perforation to remind clinicians of this rare , but dangerous , toxicity associated with this commonly used medication .
a 78-year - old woman with stage 4 chronic kidney disease ( ckd ) due to chronic pyelonephritis , and a right hypoplastic kidney was presented to our emergency department with a 2-day history of abdominal pain .
her medical history included epilepsy that was treated with carbamazepine , hypertension and hyperlipidaemia , for which she received carvedilol and atorvastatin . because of the persistent hyperkalaemia
, she was treated with calcium polystyrene sulfonate at 30 g / day ( anti - potassium granule ; assos drug , istanbul , turkey ) . as a result of the ckd ,
she was prescribed calcitriol for a mineral and bone disorder , darbepoetin alpha for anaemia and sodium hydrogen carbonate for acidosis . upon initial physical examination ,
her abdomen was non - distended with normoactive bowel sounds , but there was diffuse tenderness in her abdomen .
significant laboratory values at the time of admission included sodium 138 meq / l , potassium 4.6 meq / l , ph 7.20 , bicarbonate 13 meq / l , blood urea nitrogen 71 mg / dl , creatinine 2.6 mg / dl , leukocytes 15 500/mm , eosinophils 110/mm , haematocrit 32.7% , platelets 221 000/mm and c - reactive protein 10.9 mg / dl . on the second day of hospitalization ,
the abdominal pain worsened and free air under the diaphragm was found on abdominal radiography .
her sigmoid colon was found to be necrotic and perforated . a biopsy was performed and the perforated segment was repaired by primary closure .
the surface of the deep ulcer contained necroinflammatory debris and various sized fragments of basophilic crystalloid material with angulated margins on microscopic examination ( figure 1a and b ) .
also , there were no features of chronic colitis , including inflammatory bowel disease or chronic ischaemic colitis .
( a ) the basophilic crystalloid material in the necroinflammatory background of the ulcer surface ( haematoxylin and eosin , original magnification , 100 ) .
( b ) the basophilic crystalloid material in the necroinflammatory background of the ulcer surface ( haematoxylin and eosin , original magnification , 400 ) .
sodium polystyrene sulfonate can also bind intraluminal calcium , leading to constipation , fecal impaction and subsequent bowel obstruction or perforation .
gerstman et al .   reported a 0.27% overall incidence , with a higher incidence ( 1.8% ) during the postoperative period .
sorbitol enemas , along with experimental evidence suggesting that the necrosis was due to sorbitol rather than the kayexalate in presence of uraemia .
extensive transmural necrosis was noted in rats receiving enemas of sorbitol or kayexalate in sorbitol in both the uraemic and non - uraemic groups . as in this case report
, renal failure may be an important facilitating factor in the pathogenesis of the necrosis .
in contrast to the experimental data , our case was treated with calcium polystyrene sulfonate orally , not rectally .
rashid et al . noted that kayexalate in sorbitol given as an enema or orally to treat hyperkalaemia has been reported to induce intestinal necrosis in uraemic patients .
they studied clinical and pathologic features of 15 patients and observed kayexalate crystals in tissue specimens from surgical resections and endoscopic biopsies .
one possibility is elevated renin levels , commonly seen in renal insufficiency , that predispose the patient to non - occlusive mesenteric ischaemia via angiotensin - mediated vasoconstriction
. one gram of kayexalate possesses a theoretical in vitro exchange capacity of 23.1 meq of potassium and in vivo capacity of 1 meq .
emmett et al .   reported that in vivo potassium - binding capacity may be lower than previously estimated , more on the order of 0.40.8 meq / g of kayexalate resin .
in contrast to other minor digestive complications associated with kayexalate treatment , colonic perforation results in significant morbidity and mortality . as a result ,
potassium exchange resins may , although rarely , induce a colonic perforation , and this diagnosis should be considered in a patient treated as such in case of acute abdomen
. the clinicians must be aware of the possible rare and serious complications of potassium exchange resins .

Answer:
sodium or calcium polystyrene sulfonate ( kayexalate or analog ) is an ion - exchange resin commonly used to treat hyperkalaemia in patients with chronic kidney disease .
 it is known to cause digestive complications , such as nausea , vomiting and constipation .
 although rare , colonic necrosis and perforation are very severe complications associated with the medication . in this case report , we present a case of calcium polystyrene sulfonate - induced colonic necrosis and perforation to remind clinicians of this rare , but dangerous , toxicity associated with this commonly used medication .


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 prevalence of syphilis in the normal population has decreased significantly since 1977 in korea ( 1 , 2 ) . however ,
in western countries the incidence of syphilis has risen , mainly in the 20 - 24 age group and its clinical manifestations have been various ( 3 ) .
sexual activity has become more acceptable in our culture recently , initiating various forms of sex , and as a result , many different clinical conditions of sexually transmitted disease ( std ) have appeared .
it is usually asymptomatic and less frequently presents as proctitis , ulcer and pseudotumors ( 3 , 4 ) .
therefore , it is difficult to diagnose and physicians occasionally might prescribe inappropriate treatments ( 5 , 6 ) . in this paper
we describe a case of primary rectal syphilis which was suspected to be rectal cancer .
he complained of bowel habit change with tenesmus , mucous discharge , anal pain and intermittent presence of blood in stool .
he had a 2 cm sized , firm , non - tender and indurated nodule on the left side of the inguinal area and multiple condyloma acuminatum around the anus .
sigmoidoscopy in our gastrointestinal endoscopy unit showed two indurated masses of 1.5 to 2 cm on the posterior wall of the middle and lower rectum ( fig .
the masses had a coin like appearance , and each of them had a slightly depressed and ulcerated surface .
the vdrl quantitative test was 1:64 and the fta - abs igm and igg test was positive . a human immunodeficiency virus ( hiv )
the patient was treated with intramuscular penicillin g benzathine ( 2,400,000 iu im/1 week , thrice ) .
follow - up sigmoidoscopy after 1 month showed nearly complete regression of the chancre ( fig .
a repeat biopsy was done and the histologic result showed focal lymphoid hyperplasia . a vdrl quantitative test after 3 months was 1:1 .
most physicians have a tendency to consider rectal ulceration as a neoplasm ( 7 , 8) . similarly in our case symptoms and signs suggested rectal neoplasia and the clinical history did not reveal homosexuality .
however , after the vdrl test the patient confessed that he had been raped by a homosexual male . therefore , when rectal syphilis is suspected ( i.e. , perianal condyloma acuminatum associated with inguinal lymphadenopathy ) the history of sexual intercourse , especially rectal intercourse , has to be taken .
a dark - field examination is recommended by many studies ( 3 ) . in our case , however , a dark - field examination was not performed , because rectal chancre was highly suggested by the clinical history , anorectal lesions , pathologic findings and positive serologic test . additionally , like other syphilis cases benzathine penicillin therapy induced a rapid regression of the rectal lesions .
we believe when a positive serologic syphilis test is associated with ulcerative lesion , additional laboratory tests are not necessary .
inguinal lymphadenopathy need not require an initial biopsy when evidence of regional infection is present . usually after antibiotic therapy of at least 4 weeks
, most physicians might decide whether a biopsy is necessary . in this case , however , the physician did not have experience recognizing rectal syphilis , so he immediately obtained a biopsy specimen from the inguinal lesion .
. in western countries the incidence of rectal syphilis is rising , especially in groups of active homosexual males .
bassi et al . emphasized in his case report that endoscopists should keep in mind the rising incidence of syphilis ( 3 ) .
therefore an initial physician should encourage his / her patient to inform him / her of the patient 's sexual history .

Answer:
a 30-yr - old man was referred for suspicious rectal cancer because of ulcerated lesions in the rectum and a palpable mass in left inguinal area .
 sigmoidoscopy showed two indurated masses and histologic evaluation of biopsy revealed obliterative endarteritis with heavy plasma cell infiltration . both venereal disease research laboratories ( vdrl ) and
 fluorescent treponemal antibody absorption ( fta - abs ) tests were positive .
 after injection of penicillin g benzathine for 3 weeks , the rectal chancre and the palpable mass disappeared .


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:
keloid is a cutaneous fibrous scar that represents disequilibrium in the dermal wound healing process .
pressure therapy is used in the management of keloids , generally in combination with other therapies .
this clinical report presents use of pressure through customized appliances for therapy and prophylaxis of the ear keloids in a young female patient .
a 26-year - old female patient was referred from the department of plastic surgery for the fabrication of ear clip for ear keloid .
there was history of first ear piercing of lobe of the ears at the age of 10 years without any swelling following piercing .
additional ear piercing was done at the age of 24 years at the helix of both ears .
a small swelling appeared on the superior aspect of helix of ears bilaterally after 3 - 4 months of piercing , which gradually increased in size and continued to grow until it reached the present size on the right ear in 1 year duration .
surgical excision of keloid on the left ear was done 1 week back . on examination , a small , oval , sessile , non - tender , smooth - surfaced swelling was present on the upper part of helix of the right ear , measuring 8 mm superoinferiorly and 6 mm anteroposteriorly . on the left ear , there was a healed scar on the superior aspect of the helix .
there was no pain , pruritus , or other adverse accompanying symptoms except that it caused emotional stress due to impaired esthetics .
it was planned to use pressure therapy to reduce the size of the growth on right ear and to prevent recurrence on the left ear .
custom - made methyl methacrylate pressure appliances were planned to be used for presurgical compression of the keloid on the right ear and passive methyl methacrylate pressure appliance for preventing recurrence on the left ear .
patient 's skin over the right ear and keloid was lubricated with petroleum jelly and external auditory meatus was blocked .
impression compound ( dpi pinnacle ; dpi , india ) was used to make beading around the auricle for the confinement of the impression material [ figure 1 ]
. then thin mix of irreversible hydrocolloid impression material ( zelgan 2002 ; dentsply , india ) was poured within the confinement of the beading with patient 's head tilted opposite to the side for which impression was being made .
bell pins were placed in the partially set hydrocolloid for the retention of backing material .
thin mix of plaster of paris ( kaldent ; kalabhai karson pvt ltd , mumbai , india ) was poured over the irreversible hydrocolloid as the backing material .
the impression was poured in dental stone ( kalstone ; kalabhai karson pvt ltd ) with adequate land area to make the cast [ figure 2 ] .
a spring was designed using 21 gauze stainless steel wire that was made as a v - shaped loop with a helix at its apex and adapted over the growth on the cast .
a custom - made pressure appliance was fabricated incorporating this loop in clear methyl methacrylate and characterization was done to make the appliance more esthetically acceptable and unnoticeable to others [ figure 3 ] .
care was taken to ensure adequate space for acrylic resin between the wire loop and the skin to avoid direct contact of the stainless steel wire with the skin .
the design of the appliance involved covering the whole of the surface of the growth with gap between the two almost equal halves to permit activation in order to ensure sustained pressure , thus allowing adjustments to accommodate the reduced size and negating the need for fabrication of a new appliance .
impression compound beading around the right auricle with blocked meatus master cast of right auricle showing keloid on helix custom - made pressure appliance with spring on the right ear helix the master cast for the left ear was obtained following the same procedure as that for lubrication , blocking , and impression of the right ear [ figure 4 ] .
a custom - made passive pressure appliance was planned with incorporation of magnets for retention .
it was fabricated by adapting methyl methacrylate without any spacer , around the scar over the helix .
two pairs of 2  2 mm magnets ( tt magnets , mumbai , india ) were incorporated in the acrylic resin with two similar poles of magnets in each half [ figures 5 and 6 ] .
as there was no gap planned between the two halves of the appliance , it did not put any active pressure on the scar that could cause soreness . however
, it would prevent any growth above the surface by confinement of the soft tissue to the internal dimensions of the appliance .
post - excisional scar on the left ear helix prophylactic appliance on the scar on the left ear helix two - part prophylactic appliance incorporating magnets the appliances were finished , polished , and adjusted to remove any sore spots . these were delivered and patient was instructed to wear them all the time .
she was also instructed about their use , maintenance of hygiene , and regular follow - up .
patient was counseled about any probable post - surgical nodule and close monitoring for recurrence .
the periodic activation of the active pressure appliance was done by closing the coil of the spring .
patient was monitored for use of the appliances regularly . during follow - up , a 1 mm reduction in overall size of the right keloid was achieved after 3 months and the growth appeared shrunken in appearance [ figure 7 ] .
no other complication was observed during treatment . reduced and shrunken keloid on the right ear helix healed scar on the left ear helix
patient 's skin over the right ear and keloid was lubricated with petroleum jelly and external auditory meatus was blocked .
impression compound ( dpi pinnacle ; dpi , india ) was used to make beading around the auricle for the confinement of the impression material [ figure 1 ]
. then thin mix of irreversible hydrocolloid impression material ( zelgan 2002 ; dentsply , india ) was poured within the confinement of the beading with patient 's head tilted opposite to the side for which impression was being made .
bell pins were placed in the partially set hydrocolloid for the retention of backing material . thin mix of plaster of paris ( kaldent ; kalabhai karson pvt ltd , mumbai , india ) was poured over the irreversible hydrocolloid as the backing material .
the impression was poured in dental stone ( kalstone ; kalabhai karson pvt ltd ) with adequate land area to make the cast [ figure 2 ] .
a spring was designed using 21 gauze stainless steel wire that was made as a v - shaped loop with a helix at its apex and adapted over the growth on the cast .
a custom - made pressure appliance was fabricated incorporating this loop in clear methyl methacrylate and characterization was done to make the appliance more esthetically acceptable and unnoticeable to others [ figure 3 ] .
care was taken to ensure adequate space for acrylic resin between the wire loop and the skin to avoid direct contact of the stainless steel wire with the skin .
the design of the appliance involved covering the whole of the surface of the growth with gap between the two almost equal halves to permit activation in order to ensure sustained pressure , thus allowing adjustments to accommodate the reduced size and negating the need for fabrication of a new appliance .
impression compound beading around the right auricle with blocked meatus master cast of right auricle showing keloid on helix custom - made pressure appliance with spring on the right ear helix
the master cast for the left ear was obtained following the same procedure as that for lubrication , blocking , and impression of the right ear [ figure 4 ] .
a custom - made passive pressure appliance was planned with incorporation of magnets for retention .
it was fabricated by adapting methyl methacrylate without any spacer , around the scar over the helix .
two pairs of 2  2 mm magnets ( tt magnets , mumbai , india ) were incorporated in the acrylic resin with two similar poles of magnets in each half [ figures 5 and 6 ] .
as there was no gap planned between the two halves of the appliance , it did not put any active pressure on the scar that could cause soreness .
however , it would prevent any growth above the surface by confinement of the soft tissue to the internal dimensions of the appliance .
post - excisional scar on the left ear helix prophylactic appliance on the scar on the left ear helix two - part prophylactic appliance incorporating magnets the appliances were finished , polished , and adjusted to remove any sore spots .
she was also instructed about their use , maintenance of hygiene , and regular follow - up .
patient was counseled about any probable post - surgical nodule and close monitoring for recurrence .
the periodic activation of the active pressure appliance was done by closing the coil of the spring .
patient was monitored for use of the appliances regularly . during follow - up , a 1 mm reduction in overall size of the right keloid was achieved after 3 months and the growth appeared shrunken in appearance [ figure 7 ] .
no other complication was observed during treatment . reduced and shrunken keloid on the right ear helix healed scar on the left ear helix
keloid represents an exuberant reparative process clinically appearing as elevated nodular growth that generally does not regress spontaneously .
postoperative radiation therapy is a safe and effective therapy in reducing the recurrence of keloids after excision surgery .
better patient compliance has been observed with radiation therapy as compared to postoperative corticosteroid injections .
they are effective for prevention and treatment of keloids , especially the newer keloids , but atrophy , telangiectasias , and hypopigmentation have been the common adverse effects .
pressure therapy is used in the management of keloid scars , generally in combination with other forms of therapy .
this form of therapy was popularized after the beneficial effects of pressure stockings were observed in healing of burn scars .
pressure appliances such as various springs are used for maintaining pressure after surgical removal and to prevent post - surgical recurrence .
pressure clip is used as in conservative treatment and is an essential adjuvant for early maturation of the scar tissue and prevents the recurrence of keloid . in order to control the pressure and avoid soreness , it is mandatory to fabricate custom - made clip or stent .
the appliances described involve simplified design and use of small magnets that makes them highly retentive and stable and do not cause any pressure simultaneously .
the materials used for fabrication include acrylic resin , stainless steel wire , and commonly available magnets , making it a low - cost alternative .
this article describes a clinical report of a young female patient with ear keloid for which simple and logical therapeutic and prophylactic appliances were fabricated .
the described pressure appliance is active for the sustained compression of the keloid and passive for the prophylaxis of recurrence in surgically removed ear keloid .

Answer:
keloid is cutaneous lesion characterized by fibrous growth produced as a result of aberration in the healing process .
 pressure therapy , in combination with other forms of therapy , is used for the management of keloids .
 clips or stents are generally used for the therapy and prophylaxis .
 this report presents use of presurgical compression and prophylactic passive pressure therapy with acrylic appliances for auricular keloids in a patient .
 spring and magnets were used in the design of custom - made appliances for compression and retention .


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:
techniques and equipment to accomplish endotracheal ( et ) intubation were the precursor to modern day invasive mechanical ventilation . in recent years , however , the popularity of the et tube has waned .
clinically , the et tube is seen as an impediment to spontaneous breathing , a transit route for bacteria to the lower airway , and  with the advent of noninvasive ventilation  a device to be avoided when possible .
of particular interest has been the effect of the et tube on work of breathing and methods to eliminate this work .
commonly , pressure support ventilation ( psv ) has been suggested as the technique of choice for eliminating imposed work due to the et tube .
more recently , the technique of automatic tube compensation ( atc ) has become available to specifically address this issue . in this issue of critical care , maeda and
colleagues   compare the technique of atc , as provided by the drager evita 4 ( dragerwerks , lubeck , germany ) and the puritan bennett 840 ( carlsbad , ca , usa ) , versus psv in reducing imposed work of breathing in a lung model . before i comment on the merits of the study ,
clearly , before the advent of pressure support ventilation in the early 1980s , patients were successfully weaned using t - piece trials and intermittent mandatory ventilation , with no apparent untoward effects .
in 1986 , shapiro and coworkers   presented data from three normal volunteers breathing through et tubes at a constant tidal volume of 500 ml .
that report is widely quoted but is limited by the use of unintubated normal individuals and the requirement for a constant tidal volume during increasing respiratory rates .
additionally , close review of the data demonstrates that with a size 8.0 et tube the work of breathing in joules per minute does not become excessive until minute ventilation exceeds 15 l / min .
brochard and colleagues   compared work of breathing during assisted ventilation , four levels of pressure support , continuous positive airway pressure , and after extubation in an effort to determine the role of pressure support in overcoming the imposed work presented by the et tube . that trial evaluated both patients with normal lungs and those with chronic obstructive pulmonary disease ( copd ) . the authors concluded that the pressure support level that eliminated imposed work was between 3 and 14 cmh2o .
interestingly , this was determined retrospectively by matching the work of breathing after extubation to the level of pressure support that resulted in equivalent work of breathing during mechanical ventilation .
recent work suggests that the work of breathing postextubation may actually increase compared with work of breathing through the et tube , raising questions about the conclusion of the study by brochard and colleagues .
weissman   evaluated flow - volume loops in 18 postoperative patients intubated with size 7.0 and 8.0 et tubes and found that only ' minimal limitation to airflow ' occurred at volumes and frequencies associated with tidal breathing .
that study is one of the very few that contemplate the idea that et tube resistance may not be important when the appropriate size is chosen and the patients pulmonary function has improved to the point that weaning may be considered . of course
, there are numerous other studies that suggest that et tube resistance may represent a significant impediment to spontaneous breathing .
however , it is important to note that although there remains concern about et tube resistance , and the literature is replete with lung model studies of increased work of breathing , there is not a single clinical trial that suggests that spontaneous breathing through the et tube results in untoward outcomes .
the report by maeda and coworkers   in this issue of critical care evaluates the two most popular methods of overcoming et tube resistance , namely psv and atc .
the authors concluded that tube compensation could not overcome the pressure  time product associated with triggering and that pressure support is as effective as atc at 100% .
there are , however , tremendous disadvantages to a lung model study in comparing these techniques .
calculating the pressure  time product and work includes the work required to trigger the ventilator , which can only be overcome by direct measurement of tracheal pressure and triggering from the tracheal signal .
this method has been proposed by many , and advanced by the group from gainesville . additionally ,
although the lung model allows consistency , it can not react to differences in gas delivery . in several human studies comparing psv with atc
, the slow flow and longer inspiratory time associated with psv has been associated with dysynchrony . when used in a patient with copd ,
the patient 's high airway resistance and increased compliance allow even small amounts of psv to cause hyperinflation and auto - peep ( positive end - expiratory pressure ) .
alterations in pulmonary mechanics , along with the preference of the copd patient for short inspiratory times and long expiratory times , result in neuromechanical dysynchrony during psv .
the main proposed advantages of atc over psv are reduced work of breathing as patient demand varies , preservation of a normal , variable breathing pattern , and improved synchrony . in a recent trial of spontaneous breathing before extubation , haberthur and coworkers   failed to show any advantage of atc over psv or t - tube trials .
one issue not addressed in the study by maeda and coworkers is the role of expiratory compensation .
one distinct difference in the operation of the drager evita 4 and puritan bennett 840 is that evita 4 provides both inspiratory and expiratory compensation for et tube resistance . in these cases
, the airway pressure may be allowed to drop below peep to facilitate expiratory flow .
new modes and new techniques are developed in the hope of resolving clinical problems and often concentrate on a short - term physiologic end - point .
conventional wisdom suggests that the et tube is an impediment to efficient spontaneous breathing , yet clinical evidence during spontaneous breathing trials appears to argue to the contrary
. the real question may be whether overcoming et tube resistance is necessary , not whether atc is as good as or better than psv .
the future of atc , like many new techniques , may not be in overcoming et tube resistance , but as a method of support during spontaneous breathing that improves patient - ventilator synchrony as compared with psv .
additional clinical studies are required to complement the excellent laboratory work by the group from osaka reported in this issue .
atc = automatic tube compensation ; copd = chronic obstructive pulmonary disease ; et = endotracheal ; peep = positive end - expiratory pressure ; psv = pressure support ventilation .

Answer:
concerns about the work of breathing imposed by the endotracheal tube have led clinicians to routinely use pressure support to overcome this resistive component .
 more recently , ventilator manufacturers have introduced systems to automatically overcome endotracheal tube resistance , regardless of tube diameter or patient demand for flow . despite the theoretical advantages
 , neither method appears to provide superior performance . stepping back
 , the real question may be , is overcoming endotracheal tube resistance really important ?


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:
oculo - orbital malformations are developmental anomalies of the eye and/or ocular adnexa . in europe , its prevalence in the general population varies between 2.2 and 14 per 10,000 births.1 african studies have mainly reported cataract and congenital glaucoma as the most frequent types of eye malformations.24 malformations of the eye and orbit can be isolated or associated with other systemic malformations . to the best of our knowledge ,
the aim of this study was to describe the clinical aspects of a series of oculo - orbital malformations among children seen at the ophthalmology unit of the yaound gynaecology , obstetrics and pediatrics hospital .
we carried out a retrospective study in which all children aged 05 years who were seen at the ophthalmology unit of the yaound gynaecology , obstetrics and pediatrics hospital from january 2003 to december 2009 were included .
the medical records of all children diagnosed with a malformation of the eye and/or ocular adnexae were retained . in children with multiple malformations ,
the following variables were analyzed : age at first consultation ( diagnosis ) , sex , and the various malformations observed .
a total of 2254 children aged 05 years were examined in the ophthalmology unit during this period , and 150 of them were diagnosed with eye malformations , representing 6.65% of our consultations .
there were 78 boys ( 52% ) and 72 girls ( 48% ) , corresponding to a male - to - female ratio of 1.08 .
eye malformations were diagnosed in 71.66% ( n = 107 ) of cases during the first year of life .
table 1 presents the distribution of children according to the age at which their malformation was diagnosed .
diagnosis was made in 72.66% of cases ( n = 109 ) during the first year of life , with 11.33% of cases ( n = 12 ) diagnosed during the first month .
a total of 159 malformations were identified from the 150 files selected , considering that a child could present with one or several malformations . congenital lacrimal duct obstruction ( cldo ) was the most frequent malformation , with a total of 106 cases out of 159 ( 66.66% ) .
it was unilateral in 90 patients ( 84% ) and bilateral in 16 patients ( 15.10% ) .
congenital cataract was second , with 17 cases ( 10.69% ) , unilateral in 41.18% of cases ( n = 7 ) and bilateral in 58.82% of cases
eight cases of congenital glaucoma were diagnosed ( 5.03% ) ; it was more frequent among boys ( five boys against three girls ) .
congenital glaucoma was diagnosed in 62.5% ( n = 5 ) of cases before the age of 1 year and in 37.5% of cases ( n = 3 ) between 1 and 3 years . with regards to microphthalmos , eight cases ( 5.03% )
six cases of ptosis ( 3.77% ) were recorded and one bilateral aniridia associated with a case of congenital glaucoma without an associated systemic anomaly .
the relevance of this study lies in the fact that it is a pioneer study in this domain in cameroon .
it is intended to provide the basis for prospective studies that will specifically target each of the anomalies identified , especially the most frequent ones .
a prevalence of 1.7% was reported in nigeria by lawan2 and 2.2% in the democratic republic of the congo by kaimbo wa kaimbo et al.5 the difference between these results may be explained by the heterogeneous nature of the study population in each study .
the age group was 010 years in the study carried out by lawan ; and 025 years in that by kaimbo wa kaimbo et al .
the true prevalence of eye malformations could not be determined in this study because the total population served by this unit could not be easily assessed .
the yaound gynaecology , obstetrics and pediatrics hospital is a referral center for the management of mother - and - child diseases , and therefore the majority of children seen are referred cases .
several authors have reported that males are more affected.27 late diagnosis , which was observed in this study , might be due to the lack of attention given to suspicion of eye malformations in infants by mothers and medical practitioners .
on the contrary , studies carried out in europe report a diagnosis rate of 80% during the first week of life.8,9 in this study , congenital cldo was the most frequent malformation .
this is contrary to the studies conducted by lawan2 and bodunde and ajibode,3 both in nigeria , where cldo was the third - commonest eye malformation after congenital cataract and congenital glaucoma .
cldo among children is most often caused by failure of hasner s valve to open spontaneously.10 the majority of cases resolve spontaneously during the first year of life with massage and local antibiotic therapy.11,12 congenital cataract , which was the second most frequent malformation in this study , is the main cause of blindness and low vision among children.13 mature forms require early surgery as well as long - term and rigorous management of amblyopia , which requires the participation of the child and his / her family.14 in immature forms allowing for visual development , surgery may be delayed until the child starts learning to read or even until it becomes impossible for normal schooling.14 intrauterine infections by toxoplasmosis , rubella , cytomegalovirus , and herpes ( torch ) microorganisms , especially congenital rubella , are known for being responsible for congenital cataract.4,15 torch infection screening , although recommended during pregnancy , is not always done for several reasons : firstly , practitioners do not frequently request the tests , and secondly , even when requested , they are not done due to lack of means to pay .
cameroon is a developing country without a social security policy allowing for low - cost medical coverage .
congenital glaucoma ( figure 1 ) was diagnosed in 62.5% of cases during the first year of life .
this is less than those reported by several african studies,6,7,16 in which the diagnosis was made in 73%82% of cases during the first year of life .
it is also lower than the result obtained by zech and ravault in lyon , who reported 80% of cases before the age of 1 month.8 congenital glaucoma presents a surgical emergency , but the delay in diagnosis and hence late management in the african context might be explained by the fact that parents are ignorant about the signs .
the equal distribution between bilateral and unilateral forms is contrary to data published in the literature , where bilateral cases are more predominant .
this predominance is explained by the hereditary nature of the illness.79 microphthalmos was eight times more frequent than clinical anophthalmos ( figure 2 ) , both of which are incompatible with normal visual development resulting from an arrest in the development of the primary optic vesicles at the embryonic stage.17 with regards to ptosis , its prevalence worldwide is unknown , and it is unilateral in most cases.18 in severe cases of ptosis , the drooping eyelid can cover part of or the entire pupil and interfere with vision , resulting in amblyopia.19 bilateral aniridia is rare , with prevalence varing between 1/64,000 and 1/100,000.20,21 it is caused by a mutation in the pax6 gene , located on human chromosome 11 , and is usually associated with other eye and systemic anomalies .
cataract is found in 50%85% of patients suffering from bilateral aniridia.20 ectopia lentis , which is considered a major diagnostic criterion for marfan s syndrome,22 was found in one patient .
it is caused by a deficient development of the zonule , which like elastic tissue is of mesodermic origin.23 goldenhar syndrome ( figure 3 ) also known as oculoauriculovertebral dysplasia , is a rare congenital anomaly involving derivatives of the first and second branchial arches.24 its main ocular manifestation is limbal dermoid , which is found in 30%60% of cases and is a cause of astigmatism , amblyopia , and strabismus.25 persistent hyperplastic primary vitreous results from failure of the primary vitreous and hyaloid vasculature to regress .
its unilateral localization , which was found in this study , exists equally in literature , where it represents 90% of cases.26 other malformations , such as cryptophthalmos , iris coloboma , and the usher syndrome , described in the literature4,15 were not identified in this study .
eye malformations in children may lead to visual impairment . consequently , systematic postnatal screening for early detection and management are recommended .
close collaboration among pediatricians , general practitioners , and ophthalmologists for a multidisciplinary care approach is necessary .

Answer:
summarythe aim of this work was to describe the clinical aspects of eye malformations observed at the ophthalmology unit of the yaound gynaecology , obstetrics and pediatrics hospital.patients and methodswe carried out a retrospective study of all malformations of the eye and its adnexae observed among children aged 05 years who were seen at the ophthalmology unit from january 2003 to december 2009.resultsout of the 2254 children who were examined , 150 ( 6.65% ) presented eye malformations .
 the mean age was 14.40  4 months .
 eye malformations were diagnosed in 71.66% of cases during the first year of life .
 the most frequent malformations were congenital lacrimal duct obstruction ( 66.66% ) , congenital cataract ( 10.9% ) , congenital glaucoma ( 10.9% ) , microphthalmos ( 5.03% ) , and congenital ptosis ( 3.77%).conclusioneye malformations among children can lead to visual impairment and are a cause for discomfort to children and parents .
 therefore , systematic postnatal screening is recommended to enable early management .


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:
midaortic syndrome ( mas ) is a rare disease characterized by luminal narrowing of the abdominal aorta , and involves stenosis of the major branches in the abdomen . in 1963
, the first paper was published describing the narrowing of the descending aorta as mas , unlike takayasu 's syndrome that involves the aortic arch and leriche syndrome that involves aortic bifurcation1 ) .
clinical manifestations typically include malignant hypertension , claudication , or abdominal angina in adolescents and young adults . in children
, hypertension is an undervalued problem , which can be fatal or lead to a life - threatening emergency if untreated .
hypertension with mas is severe and often unresponsive to several antihypertensive drugs , ultimately requiring surgical intervention . here
, we report a case of a 3-year - old boy presenting with left ventricular hypertrophy , who was diagnosed with idiopathic mas following identification of severely elevated blood pressure ( bp ) .
an echocardiogram showed mild left ventricle ( lv ) hypertrophy , and he was referred to seoul national university children 's hospital for further management .
transthoracic echocardiogram revealed mild lv hypertrophy with increased lv mass index ( 89 g / m or 52 g / m , fig .
even though he did not complain of any symptoms at the time , we administered carvedilol 3.125 mg every 12 hours for lv reverse remodeling . during a routine follow - up echocardiogram 9 months later , we found abnormally increased celiac artery velocity with a diastolic tail ( peak velocity of greater than 4 m / sec , fig .
he was hospitalized for evaluation of renovascular hypertension and bp management at 4 years of age . on admission
the patient 's body weight was 21.2 kg ( > 97th percentile ) and height was 110.1 cm ( > 97th percentile ) .
his bp was high ( 206/113 mmhg in the right arm and 194/104 mmhg in the right leg ) .
a chest x - ray showed no significant cardiomegaly and a 12-lead electrocardiogram revealed lv hypertrophy ( fig .
laboratory findings on admission were as followings : serum blood urea nitrogen , 17.0 mg / dl ; serum creatinine , 0.53 mg / dl ; serum renin activity , 21.0 ng / ml / h ( reference value , < 6.7 ng / ml / hr ) ; and serum aldosterone , 39.4 ng / dl ( reference value , 335 ng / dl ) .
renal artery doppler ultrasonography showed an intermittent tardus parvus spectrogram in both renal arteries with a smaller right kidney ( fig .
3a ) . under the impression of renovascular hypertension , we performed computed tomographic ( ct ) angiography of the abdomen .
the ct angiography revealed severe stenosis at the bilateral renal artery , the ostium of the celiac branch , and the ostium of the superior mesenteric artery with diffuse luminal narrowing of the abdominal aorta into the femoral artery ( fig .
we prescribed labetalol continuous infusion , titrated up to 3 mg / kg / hr and administered concomitant oral antihypertensive medications ( amlodipine 2.5 mg twice a day and atenolol 5 mg twice a day ) to decrease the bp .
percutaneous transluminal renal angioplasty ( ptra ) was planned and abdominal aortogram confirmed diffuse luminal narrowing of the abdominal aorta into the femoral artery ( fig .
ptra was attempted with a 320 mm savvy balloon catheter via the right femoral artery ; however , the effect was unsatisfactory because of the resistance to the balloon dilatation .
he was discharged with combinations of 3 oral antihypertensive drugs ( amlodipine 2.5 mg twice a day and atenolol 12.5 mg once a day and enalapril 2.5 mg twice a day ) . at the time of discharge ,
bp was still high and measured as 134/60 mmhg in the right arm . since three years after first admission , he has been followed up at the outpatient clinic without any complications and is taking 3 combinations of antihypertensive drugs ( amlodipine 5 mg twice a day , atenolol 12.5 mg once a day and enalapril 1.25 mg once a day ) .
we described a 3-year - old boy presenting with lv hypertrophy who was diagnosed with idiopathic mas following identification of severely elevated bp . to the best of our knowledge ,
mas is prone to be referred to as hypoplasia or coarctation of the descending aorta , which presents with symptoms such as headache , claudication , and postprandial abdominal pain .
severe hypertension has been known to be the most common presentation leading to congestive heart failure , renal failure and severe lower extremities claudication7 ) .
previous studies have reported that mas is commonly diagnosed within the first 3 decades89 ) .
recently , the intensive school healthy screening system substantially aids the earlier detection in developed countries , although the patient has had no specific symptoms . moreover
, the widespread use of radiological modalities such as ct or aortography has led to the better recognition of mas .
the etiology of mas is not completely understood , and it can be congenital or acquired . congenital mas is a developmental defect that is caused by both incomplete fusion and overfusion of the paired embryonic dorsal aorta1011 ) .
the most common location of stenosis is the proximal renal artery ( up to 80% ) , and at least 25% of cases may occur in the superior mesenteric artery91112 ) .
acquired mas is caused by takayasu 's arteritis , neurofibromatosis , fibromuscular dysplasia , retroperitoneal fibrosis , mucopolysaccharidosis , and williams syndrome13 ) .
severe complications such as congestive heart failure , cerebrovascular disease , and hypertensive encephalopathy present frequently and may be fatal .
the response to antihypertensive drugs is known to be poor in hypertension with mas and several previous studies have shown vascular surgery to be the best curative therapy14 ) . as experience with ptra grows ,
however , the ptra success rate decreased with mas compared with isolated renal artery stenosis because of the extensive stenotic nature of the aorta and renal branches15 ) , even though ptra is successful in reducing hypertension by using different technical approaches in the arteries from one study3 ) . in conclusion , we report a 3-year - old boy presenting with left ventricular hypertrophy who was diagnosed with congenital mas following the identification of severely elevated bp . clinical suspicion and accurate examination , including bp measurement , would aid early diagnosis of mas and optimal treatment , and are important to prevent the fatal complications from hypertension .

Answer:
midaortic syndrome ( mas ) is a rare vascular disease that commonly causes renovascular hypertension .
 the lumen of the abdominal aorta narrows and the ostia of the branches show stenosis .
 mas is associated with diminished pulses in the lower extremities compared with the upper extremities , severe hypertension with higher blood pressure in the upper rather than lower extremities , and an abdominal bruit .
 the clinical symptoms are variable , and recognition in children with hypertension can aid early diagnosis and optimal treatment .
 hypertension with mas is malignant and often refractory to several antihypertensive drugs .
 recently , radiologic modalities have been developed and have led to numerous interventional procedures .
 we describe the case of a 3-year - old boy presenting with left ventricular hypertrophy whose severely elevated blood pressure led to the diagnosis of idiopathic mas .
 this case highlights the importance of measuring blood pressure and conducting a detailed physical examination to diagnose mas .
 this is the first reported case of idiopathic mas diagnosed in childhood in korea .


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:
because double stranded ( ds ) dna cleavage is much harder to repair than single stranded ( ss ) dna cleavage , ds damage is particularly efficient in inducing self - programmed cell death or apoptosis .
these compounds , often hailed as the most potent family of anticancer agents , produce cleavage of both strands of dna duplex via two hydrogen abstractions from two opposite strands of dna backbone by a reactive biradical , p - benzyne , generated from the enediyne core via a process , called the bergman cyclization [ 46 ] .
however , natural enediynes not only lack selectivity towards cancer cells , but also do not cause the ds cleavage with 100% efficiency .
thus , design of compounds which are capable of more efficient ds dna cleavage and combine this efficiency with selectivity towards cancer cells remains the focal point of the anticancer therapeutic agents targeting dna .
we have found that dna damaging potential of enediynes can be increased if their reactivity is tuned towards c1c5 photocyclizations , a new reaction discovered in our lab which leads to incorporation of four rather than two hydrogen atoms from the environment [ 8 , 9 ] .   because c1c5 cyclization proceeds under photochemical conditions for thermal c1c5 cyclization , see [ 10 , 11 ] , it takes advantage of the high degree of spatial and temporal controls over reactivity inherent to the photochemical activation .
the use of tissue - penetrating light allows for efficient , and selective , spatial and temporal control over prodrug activation as light can be delivered directly to the tumor when it contains a high concentration of the prodrug .
skin cancer is the most obvious target for this therapy and , in 2006 , the uk national institute of health and clinical excellence ( nice ) recommended pdt for basal cell carcinoma .
however , pdt can be also used to treat tumors on the lining of internal organs or cavities .
other tumors can be targeted with low - energy tissue penetrating photons , especially if the three - dimensional control of activation is provided by the two - photon excitation mode . for two photon excitation of enediynes , see [ 1214 ] .
in addition , this radical - anionic c1c5 cyclization of enediynes is triggered by photoinduced electron transfer ( pet ) .
this mechanistic feature increases cellular selectivity because activation is possible only in the direct vicinity of a suitable electron donor such as dna to occur . in the absence of such a donor , tfp - substituted enediynes ( scheme 1 )
we have also found that related tfp - substituted monoacetylenes are capable of photochemical alkylation of electron rich -systems [ 1517 ] and investigated whether this reaction can be also used for controlled dna - modification . a priori , efficient dna - cleavage by monoalkynes incapable of the bergman or c1c5 cyclizations can involve several possible mechanisms like base alkylation , hydrogen abstraction , generation of reactive oxygen species as well as pet .
in order to increase solubility of tfp - warheads in water and their affinity to dna , we combined them with lysine via carboxyl moiety of the amino acid , figure 1 .
importantly , this mode of attachment leaves both amino groups of lysine available for an acid - base reaction which converts them into cationic ammonium groups .
we found that dna - damaging ability of such hybrid molecules can be fine - tuned in the narrow range of physiological ph conditions which results in a dramatic increase in reactivity at the lower ph of hypoxic tumor cells .
less basic -amino group is protonated at the lower ph than 7 and this protonation not only prevents quenching the excited state of the chromophore but also provides tighter binding to negatively charged dna .
remarkably , the change in reactivity occurs at a relatively narrow and predefined ph point ( ~ph 6 ) .
these dna - photocleavers provide the dna cleavage ratios of up to the 1 : 2 ds  :  ss at ph 5.5 at concentrations and irradiation times where almost no ds cleavage is observed at the ph of healthy cells .
this dramatic increase of ds dna cleavage at the lower ph renders these molecules more efficient ds dna cleavers than calicheamicine under the conditions suitable for selective targeting of acidic cancer tissues ( figure 2(a ) ) .
we also found that the c - lysine conjugates bind selectively to nicks and gaps in a dna duplex and , upon photochemical activation , transform the easily repairable ss - dna damage into much more therapeutically important ds - dna damage   ( figure 2(b ) ) .
the medicinal potential of these molecules has been illustrated by a > 90% lncap cancer cell death induced by photochemically activated tfp - acetylene - lysine conjugate 3 in one treatment at concentrations as low as 10  nm .
similar increases in reactivity upon activation with light were observed in parallel experiments with umrc3 , umrc6 , and 786-o cancer cell lines . in summary ,
our previous work led to the development of a family of powerful and tunable dna cleaving reagents which have been shown to cleave both plasmid dna and dna oligomers outside of cells [ 15 , 18 ] .
we have also proven that these reagents can induce cancer cells death at the low concentrations . however , our previous work offered no evidence for dna - damage by tfp - enediynes and acetylenes inside of cells .
such evidence is important because cell death can result from mechanisms other than dna cleavage and because dna - cleavage of intracellular dna should be more difficult since this dna is compactly organized around histone proteins .
the aim of this work is to test the efficiency of our light - activated ds - dna - cleavers towards intracellular dna using single cell gel electrophoresis assay which can measure dna damage in individual eukaryote cells [ 2125 ] .
this assay has been used as a standard technique for evaluation of dna damage / repair , biomonitoring , and genotoxicity testing [ 2633 ] .
the cleaved dna fragments are able to migrate out of the cell under an electric field after lysis and alkali treatments while undamaged dna moves slower and remains with the confines of the nucleoid .
reagent kit for single cell gel electrophoresis assay kit , cometassay , and control cells containing different levels of dna damage , cometassay control cell , were purchased from trevigen , inc .
the cc0 sample corresponds to cells with undamaged dna whereas cc1 , cc2 , and cc3 have different levels of dna - cleavage induced with etoposide .
olympus bx61 microscope attached with the dp71 color digital camera was used to take fluorescence images of scge assay .
tail moment , the ratio of tail length to head diameter ( l / h ) , dna percentage in tail , and tail length were used to estimate dna damage .
the tail moment has been regarded as an appropriate index of induced dna damage by computerized image analysis .
it represents both the amount of damaged dna and the distance of migration by a single number .
the tail moment was calculated by multiplying the percentage of dna in the tail by the tail length ; see .
lncap cells ( p.35 ) were plated in 6 ( 100  mm ) plates at density of 250,000  cells / well and were maintained in rpmi 1640 medium supplemented with 10% fbs , sodium bicarbonate ( 2
g / l ) . when they reach 70% confluence , compound 3 was dissolved in serum - free rpmi 1640 medium supplemented with sodium bicarbonate ( 2
g / l ) . after the rpmi 1640 , medium containing the compound 3 ( 0 , 10 , and 50  m ) were added to the cells and the cells were placed in the incubator for 4 hours .
the cells were exposed to uv with cover removed for maximum exposure for 10 minutes and were trypsinized and counted .
solutions in ice cold 1 pbs ( ca and mg free ) , with 1  10  cells / ml , were prepared based on cometassay instruction from trevigen , inc .
lmagarose was melt in boiling water bath for 5 minutes and placed in 37c water bath for at least 20 minutes to cool .
cells at 1  10/ml were combined with molten lmagarose at a ratio of 1 : 10 ( v / v ) and 50  l of the mixture was transferred on cometslides .
the slides were placed at 4c in the dark for 30 minutes and they were immersed in prechilled lysis solution . after 30-minute immersion at 4c , the slides were immersed in alkaline solution prepared freshly with naoh ( 0.6  g ) , 200  mm edta ( 250  l ) , and dh2o ( 49.75  ml ) for 20 minutes at room temperature , in the dark .
then , the slides were removed from alkaline solution and washed by immersing in 1 tbe buffer for 5 minutes twice .
after adding 1 tbe buffer not to exceed 0.5  cm above slides in electrophoresis tank , the voltage at 1 volt per cm was applied for 10 minutes .
the slides were immersed in dh2o twice for 10 minutes , then in 70% ethanol for 5 minutes .
the samples were dried at 45c for 15 minutes and 100  l of diluted sybr green i was placed on the gels and the slides were stored at refrigerator .
after 5 minutes , excess sybr solution was removed by gentle tapping and the slides were completely dried at room temperature in the dark .
the control scge assay results for undamaged cells ( cc0 ) and commercially obtained cells with variable amount of dna damage ( cc13 ) are summarized in the top part of figure 3 ( entries ( a)(d ) ) .
as expected , while scge assay with healthy cells showed no tails indicative of dna damage , the assays with the damaged cells produced characteristic tails , the size of which correlates with the extent of dna damage in these cells .
with the pretreated control cells ( table 1 , ( b)(d ) ) , 33 , 47 , and 98% of dna were detected in tails , respectively .
tail moment values are also consistent with different levels of dna damage . after confirming that assay conditions work in the control cells , we proceed to investigate dna damage induced by conjugate 3 in lncap cancer cells . to find whether uv itself or thermal reactions of compound 3 may be responsible for the dna cleavage in cancer , we included two control experiments with cells exposed to uv for 10 minutes in the absence of a dna - cleaver ( figure 3(f ) ) and with cells treated with 50  m of compound 3 for 4 hours without photochemical activation ( figure 3(g ) ) .
this result confirms that neither uv nor compound 3 in the dark can damage dna under these experimental conditions .
in contrast , photochemical activation of 50  m of compound 3 produced very efficient dna damage ( more than 90% dna in the tail , table 1 ) in individual cells ( figure 3(h ) ) .
irradiation in the presence of 10  m of compound 3 also showed significant dna damage ( ~40% dna in the tail , figure 3(i ) ) .
these results confirm that compound 3 can penetrate into the nucleus of the cancer cell and damage highly compacted dna photochemically .
the concentrations of lysine conjugates used in our comet experiments are significantly higher than > 0.01  mm concentrations sufficient to cause significant photocytotoxicity to several cancer cells lines .
this difference is not limited to the comet assay  our earlier experiments with pure dna also required micromolar concentrations of the conjugate to observe the cleavage [ 18 , 19 ] .
first , it suggests ( somewhat surprisingly ) that the efficiency of cleavage for isolated plasmid dna and compacted cellular dna is not drastically different , thus indicating that our compounds should accumulate in the cell nucleus rather efficiently .
second , this observation may indicate the presence of an additional , even more efficient , mechanism for cytotoxicity which may not be based on dna cleavage .
alternatively , it may also mean that even small amount of dna cleavage ( which is not detected by the conventional , relatively insensitive assays ) is still sufficient for causing apoptosis .
although we can not distinguish between these two mechanisms at this point , this mechanistic ambiguity renders important the observation that lysine - acetylene conjugate can indeed target and damage cellular dna .
interestingly , the fluorescence images of cells treated with compound 3 ( figures 3(g ) and 3(i ) ) showed blue fluorescence in the nucleus region on top of the green fluorescence from the dna - staining dye , sybr green i. because this blue fluorescence is not observed in control cells without the conjugate , the emission is likely to result either from compound 3 itself which has the maximum emission at 440  nm ( figure 4 ) or from one of the respective photoproducts derived from the dna - photocleaver .
this observation provides additional evidence that conjugate 3 can be uptaken into the nucleus of cancer cells .
it is also interesting that there is no residual blue fluorescence in figure 3(h ) , where the dna is broken completely .
scge assays confirm the occurrence of efficient cleavage of highly compacted intracellular dna by a light - activated c - lysine acetylene conjugate .
this result provides a key mechanistic link between efficient dna cleavage and significant cytotoxicity in cell proliferation assays .

Answer:
previously , we reported the design and properties of alkyne c - lysine conjugates , a powerful and tunable family of dna cleaving reagents .
 we also reported that , upon photoactivation , these molecules are capable of inducing cancer cells death . to prove that the cell death stems from dna cleavage by the conjugates
 , we investigated intracellular dna damage induced by these molecules in lncap cancer cells using single cell gel electrophoresis ( scge ) assays .
 the observation of highly efficient dna damage confirmed that lysine acetylene conjugate is capable of cleaving the densely compacted intracellular dna .
 this result provides a key mechanistic link between efficient dna cleavage and cytotoxicity towards cancer cells for this family of light - activated anticancer agents .


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:
Using transcriptome sequencing to identify mechanisms of drug action and resistance

Paper sections:

Currently, approaches to analyze how a drug works fall into two broad categories. First, several strategies rely on model organisms that are compatible with genetic manipulations1-3. However, many drugs are inactive in these organisms, possibly due to multi-drug resistance mechanisms and target divergence4. Second, affinity-based methods are used to identify proteins that bind the drug5, 6. These approaches are effective when the drug is potent and the targets are reasonably abundant in vivo. However, establishing that a drug-binding protein is the physiological target typically depends on correlations between binding/activity assays in vitro and protein knockdown phenotypes. These correlations can be misleading due to differences between chemical inhibition, which can be acute, and the protein knockdown phenotypes, which can be indirect or from cumulative effects7. Currently, we lack an approach that addresses these limitations and can determine mechanisms of drug action in human cells.

The 'gold standard' in identifying a drug's target is achieved when two criteria are met. First, resistance to a drug in a physiological context occurs through mutation in the target protein. Second, this mutation should suppress inhibition of the target's activity by the drug. This standard is met for a few drugs (e.g. Gleevec), for which focused analyses of the expected target led to such mutations8, 9. However, the human genome's large size and complexity has limited unbiased analyses of mutations conferring drug resistance.

We sought to develop an approach that could achieve 'gold standard' validation of a drug's target and be applied to relevant human cell types (e.g. cancer cells). We reasoned that deep sequencing and bioinformatics could be used to screen the genome of drug resistant clones isolated from cultured human cells for resistance mutations. Moreover, we hypothesized that analyzing mutations common to multiple clones would focus our analysis on a handful of potential drug targets. When combined with biochemical analyses, these data could lead to 'gold standard' validation of the drug's physiological target. As a proof-of-concept we analyzed the mechanisms that confer resistance to drugs whose targets are known.

BI 2536 (Fig. 1a) is currently in clinical trials and inhibits Polo-like kinase 1 (PLK1), a major cell cycle regulator10. To isolate resistant clones we used a human colon cancer cell line, HCT-116, which is deficient in mismatch repair and has low expression of multi-drug resistant (MDR) pumps11. Therefore, HCT-116 behaves like a mutagenized cell line, facilitating the rapid identification of mutations that confer drug resistance12, 13. From fifteen BI 2536-resistant clones (isolated from selections with 10 nM BI 2536, LD50: 3.9 ± 2.8 nM), we selected six for transcriptome sequencing (also called RNA-seq). The LD50s for BI 2536 were 3-9 fold higher in these clones than in the parental cell line (Fig. 1b, Supplementary Results, Supplementary Table 1). In parallel, the parental cell line was also processed for transcriptome sequencing.

The sequencing data were analyzed to identify single nucleotide variations and short insertions/deletions (indels) in each clone, and only those present in coding sequences were further considered. We found 6-14 single nucleotide variations that were significantly increased (with a 0.5% false discovery rate) in the BI 2536-resistant clones, compared to the parental cell population (Supplementary Tables 2-7; no indels were found). Groups of similar clones were identified by analyzing single nucleotide variations using a clustering approach (see Supplementary Methods). Among the six clones, A, B, and C were independent (groups 1, 2, and 3, respectively), while D, E, and F formed a single group (group 4, Fig. 1c). We further focused our analysis on genes that were mutated in more than one BI 2536-resistant group. While there were no genes common to all groups, PLK1 was the only gene mutated in more than one group (Supplementary Table 8).

Two distinct PLK1 mutations were identified, G63S and R136G, both of which map to the binding site of BI 2536 in the crystal structure of PLK1 (Supplementary Fig. 1)14. To examine whether these mutations are sufficient for conferring resistance to BI 2536, we generated stable cell lines expressing wildtype PLK1 and each mutation as a GFP-tagged full-length PLK1 construct. Independent cell lines were used as secondary mutations were less likely to be common between these lines and HCT-116. The R136G mutation suppressed BI 2536 toxicity in hTERT-RPE1 (Fig. 1d), and the G63S mutation suppressed toxicity in hTERT-RPE1 (Fig. 1d) and in HeLa cells (Supplementary Fig. 2). These data suggest that PLK1 is the major physiological target of BI 2536. Published data show that the R136G mutation has reduced sensitivity to BI 2536 in vitro15. Therefore, these data provide the 'gold standard' proof that PLK1 is the target of BI 2536.

BI 2536-resistant group 4 (representing clones D, E, and F) did not have a mutation in the PLK1 gene, suggesting a different resistance mechanism. An unbiased survey of all transcript levels (Supplementary Data 1 and 2), which can be determined from the transcriptome sequencing data, revealed that ABCB1 (P-gp, a drug efflux transporter) was among the most highly over-expressed mRNAs in group 4 clones (Supplementary Fig. 3). Consistent with the hypothesis that the intracellular concentration of BI 2536 was lowered by increased drug efflux, group 4 clones also had reduced sensitivity to the chemically-unrelated drug taxol, a compound known to be transported by the ABCB1 pump16 (Fig. 1e). While further experiments are needed to confirm this resistance mechanism, our data suggest that our approach can lead to testable hypotheses for indirect mechanisms of drug resistance.

We next examined if our approach could be applied to another drug. Bortezomib (Fig. 2a) inhibits the proteasome by targeting its subunit PSMB5 and is used clinically to treat multiple myeloma and mantle cell lymphoma17. Nineteen clones were isolated from HCT-116 cells grown in the presence of bortezomib (8 -12 nM, LD50: 6.3 ± 0.9 nM). Five clones, with reduced bortezomib sensitivity (LD50s 2.4 – 6.5 fold higher, Fig. 2b and Supplementary Table 9), were processed for transcriptome sequencing. 15-28 single nucleotide variations in each clone were identified (Supplementary Tables 10-14). Clustering analysis (Fig. 2c) grouped clones A, B, C, and D together (group 1) while clone E was independent (group 2). Five genes were mutated in both bortezomib-resistant groups, and the only gene with two distinct mutations (M104V and A108T) was PSMB5, the known target of bortezomib (Supplementary Table 15). If the drug target was unknown, all five genes would have to be examined as potential targets. However, the existence of two distinct resistance mutations would make PSMB5 the highest priority for further analysis.

We found that expression of GFP-tagged PSMB5, carrying either of these mutations, suppressed bortezomib sensitivity in an independent cell line (hTERT-RPE1, Fig. 2d). This is consistent with previous reports that A108T confers bortezomib-resistance18, 19. As both mutations in PSMB5 map to the drug's binding site, we hypothesize that they directly suppress drug interactions (Supplementary Fig. 4)20. While additional biochemical tests are needed to examine this further, our data indicate that our strategy can efficiently lead to resistance mechanisms that include a drug's direct target.

Our analysis thus far indicates that for our approach to be effective, resistance via mutations in a drug's direct target must occur at high frequency in drug-resistant clones. To examine this, we sequenced the PLK1 gene in each of the nine BI 2536-resistant clones that we had not processed by RNA-seq. PLK1 was mutated in ~45% of these clones (4 of 9, Supplementary Table 16). We next analyzed two kinesin-5 inhibitors, S-Trityl-L-cysteine (STLC), which is known to be selective21, and 4-(2-(1-phenylcyclopropyl)thiazol-4-yl)pyridine (PCTP), which has been shown to inhibit other related motor proteins in vitro21, 22. Kinesin-5 mutations were found in ~30% of the STLC-resistant clones (4 of 14, Supplementary Fig. 5) and in ~15% of PCTP resistant clones (3 of 22, Supplementary Fig. 6). These data indicate that resistance in a drug's direct target occurs at high frequency when a drug has one major physiological target (as is the case for STLC, BI 2536 and bortezomib). When a drug has multiple targets (e.g. PCTP) it is likely that resistance in a single target will be less frequent and our approach may be limited as a greater number of clones would have to be sequenced to identify mutations common in more than one clone.

In summary, we have developed a method to identify the target of drugs in human cells by examining resistance mechanisms. Our strategy (Fig. 2e) involves isolating multiple drug resistant clones from genetically heterogeneous human cells. Clones with multi-drug resistance can be excluded by testing for reduced sensitivity to unrelated compounds (i.e. taxol). The remaining clones are processed for transcriptome sequencing, along with the parental (untreated) cell population. Bioinformatics is used to find genes mutated in more than one independent clone. These genes are prioritized for further biochemical and cell biological analyses to identify the drug's direct target and indirect resistance mechanisms.

Our strategy has advantages over other approaches to identify a drug's target. First, unlike many other target identification approaches, our method does not rely on chemical modifications of the drug of interest. This can be important when small changes in a drug's chemical composition can alter its mechanism of action23. Second, our approach can enable cell-type specific analyses, which would be particularly useful if a drug is toxic in specific tissues. While our approach is currently limited to analyzing cytotoxic drugs, it should be possible to extend its use to non-toxic drugs by using phenotypic or reporter-based read-outs to select clones with reduced drug sensitivity (e.g. change in fluorescence). Furthermore, as our approach focuses on discovering single nucleotide variations and insertions/deletions, it does not report on all potential mechanisms of resistance. This limitation can be addressed by combining our strategy with other genomic methods, such as exome capture, full genome sequencing, and bisulfate conversion followed by sequencing (to detect DNA methylation). Our approach has the potential to reveal the physiological on-targets of a drug in disease cells, unintended off-targets in healthy cells, and can reveal cellular mechanisms of drug resistance. These findings can impact chemical modifications of drugs to improve efficacy and limit toxicity. When unanticipated drug targets are found new uses of the drugs may also be suggested.

Answer: Determining mechanisms of drug action in human cells remains a major challenge. Here we describe an approach in which multiple drug resistant clones are isolated and transcriptome sequencing is used to find mutations in each clone. Further analysis of mutations common to more than one clone can identify a drug\xe2\x80\x99s physiological target and indirect resistance mechanisms, as indicated by our proof-of-concept studies of cytotoxic anti-cancer drugs, BI 2536 and bortezomib.


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:
suicide is a grave public health issue with a global mortality rate of 16 per 100,000 individuals.1 suicide is one of the top three leading causes of death , particularly among individuals aged 1544 years , which is a productive age group.1 suicide is a complex event that is influenced by biological , cultural , psychological , and socioeconomic factors .
more than 90% of suicide victims were diagnosed with psychiatric problems at the time of death , and approximately two thirds had been diagnosed with depression.2,3 depressed patients tend to consult physicians other than psychiatrists , and a variety of medical professionals , including general practitioners , the staff of emergency departments , and non - psychiatric nurses , are key interveners for preventing suicide . among medical staff members , negative attitudes toward suicide such as
anger could affect nontherapeutic reactions to suicidal individuals.4 furthermore , a belief that suicide is a personal right was negatively related to suicide intervention skills.5 an accurate assessment of the attitudes toward suicide held by medical staff members is relevant .
previous studies have shown that difficulties with parental bonding during childhood could be a predisposing factor for the onset of many psychiatric conditions , such as anxiety , depressive states , and maladjusted behaviors.68 parental bonding and premorbid personality traits play an important role in shaping the developmental trajectory of an individual , including his / her ability to adjust to stressful events .
although few studies have assessed the relationship between parental bonding and mental conditions among medical staff members,9,10 no study has evaluated the association between parental bonding and attitudes toward suicide .
the objective of this study was to investigate whether parental bonding is associated with attitudes toward suicide among medical college students in japan .
students in their fifth year of medical school at hirosaki university , hirosaki , japan , participated in the study .
the surveys were distributed to 226 medical students . of the distributed 226 surveys , 160 questionnaires ( 116 males and 44 females )
the demographic data ( age and sex ) were obtained from self - questionnaires and interviews .
the data collection for this study was approved by the ethics committee of the hirosaki university school of medicine , and the subjects provided written informed consent before participating in the project . the parental bonding instrument ( pbi )
was administered to each participant to measure the attitudes and behavior of the parents.11 the pbi is a 25 item self - rating instrument by which individuals over the age of 16 report their experiences of being parented to the age of 16 .
a total of 12 items measure the dimension of care , and 13 items measure protection , both on a likert scale .
the care dimension of the pbi reflects parental warmth and involvement in contrast to rejection and indifference .
the overprotection dimension of the pbi reflects parental overprotection and control in contrast to the encouragement of autonomy .
higher scores on the care and protection dimensions reveal that participants perceive their parents to be more caring and/or protective .
we employed the japanese version of the attitudes toward suicide questionnaire ( atts ) to assess the attitudes toward suicide held by the study participants.12 we employed a six factor model that was previously developed in studies of japanese attitudes , including
 common occurrence  ,  suicidal expression as mere threat  ,  unjustified behavior  ,
impulsiveness.12,13 each item , with the exception of items 10 and 28 , was scored on a five point scale from 1 ( strongly agree ) to 5 ( strongly disagree ) .
items 10 and 28 were scored using a different scoring method that employed a five point scale from 1 ( strongly disagree ) to 5 ( strongly agree ) .
multivariate regression analysis was applied to assess the relationship between parental bonding and attitudes toward suicide .
the data were analyzed using the pasw statistics software program for windows , version 18.0 .
students in their fifth year of medical school at hirosaki university , hirosaki , japan , participated in the study .
the surveys were distributed to 226 medical students . of the distributed 226 surveys , 160 questionnaires ( 116 males and 44 females )
the demographic data ( age and sex ) were obtained from self - questionnaires and interviews .
the data collection for this study was approved by the ethics committee of the hirosaki university school of medicine , and the subjects provided written informed consent before participating in the project .
the parental bonding instrument ( pbi ) was administered to each participant to measure the attitudes and behavior of the parents.11 the pbi is a 25 item self - rating instrument by which individuals over the age of 16 report their experiences of being parented to the age of 16 .
a total of 12 items measure the dimension of care , and 13 items measure protection , both on a likert scale .
the care dimension of the pbi reflects parental warmth and involvement in contrast to rejection and indifference .
the overprotection dimension of the pbi reflects parental overprotection and control in contrast to the encouragement of autonomy .
higher scores on the care and protection dimensions reveal that participants perceive their parents to be more caring and/or protective .
we employed the japanese version of the attitudes toward suicide questionnaire ( atts ) to assess the attitudes toward suicide held by the study participants.12 we employed a six factor model that was previously developed in studies of japanese attitudes , including
 common occurrence  ,  suicidal expression as mere threat  ,  unjustified behavior  ,
impulsiveness.12,13 each item , with the exception of items 10 and 28 , was scored on a five point scale from 1 ( strongly agree ) to 5 ( strongly disagree ) .
items 10 and 28 were scored using a different scoring method that employed a five point scale from 1 ( strongly disagree ) to 5 ( strongly agree ) .
multivariate regression analysis was applied to assess the relationship between parental bonding and attitudes toward suicide .
the data were analyzed using the pasw statistics software program for windows , version 18.0 .
table 1 presents the items included in the six factor atts with their descriptive data .
paternal care was significantly associated with paternal protection , maternal care , maternal protection , and right to suicide .
maternal care was significantly associated with maternal protection , right to suicide , and common occurrence .
right to suicide was significantly associated with common occurrence , unjustified behavior , and preventability / readiness to help .
table 3 shows the multiple regression analysis of the atts sub - scales with the pbi scores . after adjusting for age and sex ,
maternal care approached a statistically significant association with the right to suicide . under the same conditions , maternal care
the present study assessed attitudes toward suicide and their associations with parental bonding among japanese medical college students .
the majority of the participants in our study agreed that anyone could commit suicide ( 88.8% ) and that suicide is preventable ( 86.3% ) .
in addition , the multiple regression analysis revealed that participants who reported a higher level of maternal care thought that suicide was a common occurrence and tended to think that people do not have the right to commit suicide .
domino and takahashi used the suicide opinion questionnaire to investigate the differences in attitudes toward suicide between students in japan and those in the united states , and the results demonstrated that the scores for  right to die  and  normality  were higher in japanese students and that those for  aggression  were higher in american students.14 etzersdorfer et al compared the attitudes towards suicide held by medical students in madras with those in vienna , finding that medical students in madras rejected the right to commit suicide and assisted suicide to a greater degree than the students in vienna.15 in a swedish study to assess whether attitudes differ between students at the beginning and end of their studies , students in the final year of medical school more frequently considered suicide to be an expression of psychiatric disease and thought that people attempting to commit suicide were not responsible for their actions.16 in addition , a study from japan revealed that sympathetic comments increased with the amount of years in school among students while critical comments decreased.17 in japan , mentality on suicide might be more culturally visible and acceptable than other countries . in past years , suicide was regarded as an honorable solution to personal guilt and failure . regarding occupational differences in attitudes toward suicide ,
onc et al found that medical students and general practitioners held the most permissive attitudes in turkey.18 in addition , they showed that the attitude scores of general practitioners regarding their preparedness to prevent suicide were lower compared to those of other groups . in japan , kodaka et al reported attitudes toward suicide among pharmacists using the atts.13 more than half of pharmacists reported that people understand the wishes of others to commit suicide , and 16.8% of the participants thought that people who mention suicide do not actually take their own lives .
a 10 year follow - up study of norwegian physicians ( n=631 ) revealed that a low level of maternal care predicted severe depressive symptoms and partially mediated low self - esteem.9 lung et al assessed the psychological effects on 127 health care workers who had cared for suspected severe acute respiratory syndrome ( sars ) patients .
early maternal attachment and neuroticism were found to heavily affect mental health during life - threatening stress.10 distinct patterns of parental bonding may contribute to the development of different dysfunctional schemas which may influence attitudes toward suicide.19 there are several limitations in this study .
first , we used pbi to assess the child rearing behavior experienced by our participants .
although pbi has shown basic reliability for long periods,20 we could not completely rule out possible influences of the current mood state or recall bias in individuals because pbi is an instrument for measuring recalled parental behaviors .
second , certain parameters were not assessed in this study personality traits , a history of psychiatric disorders , suicidal behavior , and current mood state could affect the attitude towards suicidal behavior . third , because the participants in our study are medical students , we can not generalize these results to general practitioners .
our study indicated that the majority of participants seriously believe that anyone could commit suicide .
participants who have experienced a higher level of maternal care thought that suicide occurs commonly and tended to think that people do not have the right to commit suicide .
although parental bonding predisposes these attitudes toward suicide , educational programs could change caretaking practices.21 to achieve more positive attitudes towards suicidal behavior , promoting the best practices for suicide prevention is needed for medical students .

Answer:
backgroundsuicide is a grave public health issue that is responsible for a high mortality rate among individuals aged 1544 years .
 attitudes toward suicide among medical staff members have been associated with appropriate therapeutic responses to suicidal individuals .
 the aim of this study was to examine the effects of parental rearing on attitudes toward suicide among japanese medical college students.methodswe examined the association between parental bonding and attitudes toward suicide in 160 medical college students in japan .
 the parental bonding instrument was used to assess the attitudes and behaviors of parents .
 the attitudes toward suicide were evaluated using the japanese version of the attitudes toward suicide questionnaire.resultsthe mean age of the subjects was 25.24.0 years old .
 the majority of the participants in our study agreed that anyone could commit suicide ( 88.8% ) and that suicide is preventable ( 86.3% ) . after adjusting for age and sex , multivariate regression analysis revealed that maternal care approached a statistically significant association with the  right to suicide  attitude . under the same conditions ,
 maternal care was shown to be significantly associated with the  common occurrence  attitude .
 no other significant relationships were observed between parental bonding and attitudes toward suicide.conclusionthis study suggests that a higher level of maternal care ensures that children think that suicide occurs less commonly .
 the promotion of best practices for suicide prevention among medical students is needed .
 child rearing support might be associated with suicide prevention .