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:
Selective functionalization at N 2 -position of guanine in oligonucleotides via reductive amination

Paper sections:

Methods to synthesize modified oligonucleotides are of prime importance due to their role in a variety of applications. For example, modified oligonucleotides are useful to understand the effect of specific chemical modifications on nucleic acid stability, ability of DNA to replicate, and to study nucleic acid-protein interactions. [1][2][3][4] In addition, modified oligonucleotides also have diagnostic or therapeutic applications; for example in nucleic acid sequencing and identification, or in small interfering RNA technology for enhanced stability and target affinity in vivo. 5 However, selectively modified oligonucleotides are difficult to obtain, and are most commonly synthesized on a solid-phase using the corresponding phosphoramidite derivative. The synthesis of the desired phosphoramidite, in turn, involves several steps including nucleotide protection and deprotection, and purification processes such as ion exchange and HPLC. This makes the overall process challenging, time-consuming, and expensive.

One approach to circumvent this problem is to introduce the desired modifications after DNA (or RNA) synthesis. However, this would require methods that can chemoselectively target one out of the four nucleobases. Although a number of reagents are known to form adducts with DNA 6,7

, very few chemical methods exist for selective targeting of one nucleobase over others. One such example was reported by Okamato et al., in which they showed that 5-methylcytosine, an important epigenetic modification, can be sequence selectively oxidized using osmium based reagents for the selective cleavage of a DNA strand. 8 In another example, Geigle et al. have performed selective modification at the O 6 position of guanine in DNA using metal carbenes.

9

The selective modification of guanine in DNA is biologically relevant. In particular, modifications at the N 2 -position of guanine frequently lead to mutagenic DNA adducts, and the availability of such substrates is essential to elucidate the biological ramifications of adduct formation. Recently, N 2 -modified deoxyguanine oligonucleotides were used as substrates to study the activity of the enzyme Top1, which is highly susceptible to modifications in the DNA bases. 10 Guanine nucleotide and its derivatives are also interesting as they self-assemble to form higher order structures in the presence of some metal ions. These have a variety of applications as anticancer hydrogels 11 , inducers of effective cell growth 12 , and selective absorption of anionic dyes from water 13 . These properties can be tuned by appropriate chemical modifications. Moreover, substituted guanine containing deoxy-oligonucleotides have been shown to efficiently fold into G-quadruplexes, biologically relevant structures comprised of four G-rich DNA strands. The modified G-quadruplexes have several desirable characteristics like enhanced thermal stability, 14 and anti-thrombin and anti-HIV properties. 15,16 Antisense oligonucleotides containing guanine, substituted at its N 2 -position with cationic groups, show enhanced DNA (and RNA) binding, while preserving RNase H activity required for gene silencing. 17,18 In summary, the utility of N Despite its importance, very few reagents are available for the post-synthetic functionalization of the exocyclic amine of guanine nucleotide selectively over other nucleotides. Although previous studies have reported reductive alkylation of the exocyclic amine of guanine derivatives, 19,20,21 a systematic study of the reactivity and selectivity of the exocyclic amine of guanine in a complex chemical environment such as DNA is lacking. The availability of chemical methods for guanine N 2 modification are particularly important as the N 2 -alkyl deoxyguanine nucleotides are not substrates for DNA polymerases (except for polymerase κ 22), precluding the use of enzymatic methods for modified nucleotide incorporation into DNA. Here, we have systematically studied reductive amination of guanine with various aliphatic aldehydes to selectively make guanine N 2 substituted DNA oligonucleotides. We show that this simple yet powerful reaction can selectively modify the N 2 -position of guanine, leaving the other aromatic exocyclic amine bases (viz. cytosine and adenine) unaffected under the reaction conditions.

We first treated an aqueous solution of each of the four nucleotide monophosphates (NMPs) individually with propanal in the presence of sodium cyanoborohydride (Table 1). Near quantitative conversion was obtained for guanine (both dGMP and GMP) to give the monoalkylated product after six hours. The product identity and site of the reaction was confirmed by NMR methods. The product assignment was further supported by the observation that inosine triphosphate (ITP), lacking the N 2 amine, did not react under these conditions. Under the same reaction conditions, no conversion was observed for adenine and cytosine nucleotides, both of which contain an exocyclic amine, even after 24 hours, indicating that the reaction was selective for guanine (Table 1). Similarly, uracil and thymine derivatives did not react under these conditions. We also treated a mixture of all the four deoxy NMPs (dNMPs) under the given reaction conditions. After 6 hours, the crude reaction mixture was analysed by HPLC, which indicated that even in the mixture, only dGMP successfully reacted with propanal to form N 2 -propyl substituted dGMP, while others remained unchanged (Fig 1). Not surprisingly, screening several aliphatic aldehydes in this reaction revealed that the reaction became more sluggish as the hydrophobicity of the aldehyde increased. This was likely due to the reduced solubility of the aldehyde in aque-ous medium, and correlated well with the calculated logP values for the aldehydes. In agreement with this, we also found no reaction with aromatic aldehydes under the same reaction conditions.

Although the exact reason for selectivity towards guanine needs to be investigated, it is likely that the N 2 -amine of guanine is significantly more nucleophilic, as it is part of a guanidinium system. In comparison, the amidines of cytosine and adenine are less nucleophilic. 23,24 We further note that aliphatic ketones showed negligible reactivity with guanosine under the given reaction conditions, indicating that in addition to the reactivity of guanine, electronic and steric properties of the carbonyl substrate also play an important role in differentiating the exocyclic amine of guanine. The selectivity observed for guanine was remarkable because of the ability of a simple reaction to distinguish between GMP/dGMP and other nucleotide bases, indicating that this reaction could potentially be applied to post synthetic modification of oligonucleotides, allowing guanine base to be selectively targated. To test this idea, we started with a four nucleobase DNA sequence containing all four nucleotides, i.e., d(GTCA). When this oligonucleotide was treated with propanal and NaCNBH 3 , a new peak appeared in HPLC, but complete consumption of the starting material was not observed. So, we performed systematic optimization of the reaction conditions, including temperature and reagent concentrations. We found that although an increase in temperature up to 45°C increased yield to 70%, any further increase led to significantly lower yields likely due to decomposition of the reducing agent. In contrast, increasing aldehyde concentration pushed the reaction towards completion, with almost complete disappearance of starting material within 3 hours, and appearance of a new peak in the HPLC profile (See Fig. 2, and Table 2). A mass spectrometric analysis of this peak showed a single propyl modification in the oligonucleotide, and was consistent with a modification on guanine. We note that even at 1500-fold excess of aldehyde, other nucleobases remained unreacted.  DNA concentration was 5 mM in water, a % conversion was calculated based on area under the peak with respect to starting material; b reaction was stopped after 8 hours since there was no significant change in % conversion after 3 hours.

We then tested a series of DNA oligonucleotides using the above reaction protocol, and found that method works efficiently with all tested DNA sequences irrespective of the position of guanine, and the number of cytosine and adenosine bases (Table 3). In all G-containing oligonucleotides, a new peak appeared in the RP-HPLC profile indicating likely formation of one new product in the reaction mixture. This new peak was attributed to reaction at the single guanine site, as oligonucleotides lacking guanine did not show any change in HPLC profile after six hours (Table 3, Entry ODN5, ODN7, ODN10). To further confirm this result, ODN11 was treated with phoshodiesterase I from Crotalus adamanteus venom followed by calf intestine phosphodiesterase (CIP) digestion. This treatment hydrolyzes the DNA into individual nucleosides and allows product identification by HPLC. Analysis of the hydrolyzed products showed the presence of N 2 -propyl deoxyguanosine nucleoside, along with other unreacted deoxynucleosides (dC, dT and dA). Taken together, the data presented above strongly support that the reaction takes place regio-and chemo-selectively at the N 2 -position of guanine in DNA, leaving all other nucleobases unaffected. We applied this reductive amination strategy to functionalize a G-quadruplex forming sequence TT(GGGT) 4 . A mass spectrometric analysis of the modified sequence showed that eleven out of the twelve guanine bases were modified, indicating the potential of this reaction to densely functionalize DNA. When oligonucleotide ODN11 was treated with more hydrophobic aliphatic aldehydes, the reaction was sluggish, and the % conversion was significantly reduced for aldehydes having logP more than 1.5 (Table 4). We further explored the potential of this reaction to introduce bioorthogonal handles such as azide or alkyne into a DNA oligonucleotide (Table 4). Aldehydes with suitable bioorthogonal handles reacted with ODN11 to give moderate to good yields of the monosubstituted product. The bioorthogonal functionality introduced on oligonucleotides in this manner can be further reacted with a desired probe for example a fluorophore or affinity tag to obtain labeled oligonucleotides. We have demonstrated this using dibenzylcyclooctyne-PEG 4 -5/6-tetramethylrhodamine (DBCO-TAMRA) as a representative example to illustrate the scope of the reaction. We first reacted ODN11 with 5-azido-1-pentanal, and the product was washed with ethyl acetate to remove organic reagents. The bioorthogonal handle containing DNA was further reacted with DBCO-TAMRA under strain mediated copper free click conditions. The formation of the fluorescently labeled DNA was confirmed by HPLC, as well as HRMS (Fig. 3). Oligonucleotide used is d(AACTGACTCA). DNA concentration was 5 mM in water; aldehyde = 1500 equiv. and NaCNBH3 = 150 equiv. w.r.t DNA; conversions are based on area under the peak (λ = 253nm). In summary, we have shown that reductive amination with DNA bases can selectively modify guanine in nucleic acids. This simple yet powerful method can readily produce oligonucleotides modified at the N 2 -position of guanine. We have also shown an application of this method to access fluorescent DNA labeled specifically at guanine base. The method is simple and readily accessible even for biologists, and significantly reduces the time and cost involved in using modified phosphoramidites for selective labeling of guanine in nucleic acids.

Answer: Chemo-and site-specific modifications in oligonucleotides have wide applicability as mechanistic probes in chemical biology. Here we have employed a classical reaction in organic chemistry, reductive amination, to selectively functionalize the N 2 -amine of guanine/2'-deoxyguanine monophosphate. This method specifically modifies guanine in several tested DNA oligonucleotides, while leaving the other bases unaffected. Using this approach, we have successfully incorporated desired handles chemoselectively into DNA oligomers.


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:
bartter syndrome ( bs ) is a rare inherited renal tubular disorder characterized by renal salt wasting , hypokalemic metabolic alkalosis and normotensive hyperreninemic hyperaldosteronism1 , 2 ) . although bs is a typical tubular disorder ,
there have been several case reports of patients who developed focal segmental glomerulosclerosis ( fsgs ) , a glomerular lesion , during the course of bs3 - 7 ) .
such cases support a possible link between the two diseases , and indicate that stimulation of the renin - angiotensin system ( ras ) and increased angiotensin ii in response to chronic glomerular hyperfiltration due to salt - losing tubulopathy may lead to secondary fsgs3 , 4 , 8) .
in addition to fsgs , several other factors have been reported to influence the renal survival of patients with bs , including recurrent episodes of dehydration during early infancy , chronic hypokalemia , long - term use of non - steroidal anti - inf lammatory drugs , nephrocalcinosis , and mutations in the bsnd gene9 - 11 ) .
however , there have been only a few case reports of patients with bs who underwent renal transplantation6 , 12 - 15 ) . here ,
we present a case of a patient with bs who developed fsgs and subsequently underwent renal transplantation due to aggravation of his renal function .
we also review previously reported cases of both diseases and cases of individuals with bs who underwent renal transplantation .
there were no perinatal problems including polyhydramnios , and the family history was unremarkable . at age
3 months , the patient visited a hospital due to recurrent febrile episodes and poor weight gain . the patient was diagnosed as bs , and potassium supplement and indomethacin medication were started . however ,
his compliance to the drug was very poor . detailed clinical and laboratory data from that time are unavailable . at age 7 , proteinuria was incidentally detected upon routine follow - up urinalysis .
a renal ultrasonography revealed diffusely increased parenchymal echogenicity without definite evidence of nephrocalcinosis or nephrolithiasis . at age 8 ,
a renal biopsy was conducted at the hospital due to persistent proteinuria ( 24-hour urine protein excretion 3,840 mg / day , serum albumin 3.4 g / dl , and serum creatinine 1.2 mg / dl ) .
his proteinuria did not respond to 4 weeks of oral prednisolone ( 2 mg / kg / day ) treatment . at age 10 ,
the patient 's height was 123 cm ( < 3rd percentile ) , weight was 36 kg ( 90 - 97th percentile ) , and blood pressure was 117/69 mmhg at the time of admission .
the laboratory examination revealed a serum creatinine level of 3.1 mg / dl , a sodium level of 138 mmol / l , a potassium level of 3.7 mmol / l , a chloride level of 103
mmol / l , a bicarbonate level of 30 meq / l , a magnesium level of 2.0
/ ml / hr ( normal range 1 - 2.5 ) , an aldosterone level of 558 pg / ml ( normal range 50 - 194 ) , and a spot urine calcium ( mg ) to creatinine ( mg ) ratio of 0.02 . additionally , the patient 's bone age was 6 years 5 months upon admission .
genetic analysis revealed a homozygous p.trp(tgg)610stop(tga ) mutation in exon 16 on the clcnkb gene .
his renal function deteriorated progressively for one year thereafter , at which point hemodialysis was started .
subsequently , the patient underwent renal transplantation successfully from a deceased donor at age 16 .
the post - transplantation course has been uneventful for more than 3 years , with complete disappearance of bs without recurrence of fsgs .
clinically , bs can be classified into two variants , antenatal / neonatal bs and classic bs according to the onset age .
genetically , bs can be classified into at least 5 subtypes according to underlying mutant genes , all of which are expressed in the tubular epithelial cells of the thick ascending limb of the loop of henle .
bs type i is caused by loss - of - function mutations of slc12a1 encoding the apical sodium - potassium - chloride cotransporter ( nkcc2 ) , while bs type ii is caused by loss - of - function mutations of kcnj1 encoding the apical inwardly - rectifying potassium channel ( romk ) , bs type iii is caused by loss - of - function mutations of clcnkb encoding the basolateral chloride channel ( clc - kb ) , bs type iv is caused by loss - of - function mutations of bsnd encoding barttin , and bs type v is caused by gain - of - function mutations of casr encoding the basolateral calcium sensing receptor ( casr)2 ) .
bs is an inherited tubular disorder ; however , our patient developed fsgs , an acquired glomerular lesion , later in the disease course .
there have been five similar case reports of bs complicated by fsgs3 - 7 ) ( table 1 ) .
in addition , there is an additional report of a patient with classic bs who developed end - stage renal disease due to glomerulopathy12 ) .
however , this patient was excluded from the review because the renal pathology was described as ' diffuse ' glomerulosclerosis . as shown in table 1 ,
patients with bs and fsgs show development of fsgs independently of gender , clinical variants of bs or genetic subtypes of bs .
one patient had nephrocalcinosis , and three patients had a history of long - term non - steroidal anti - inflammatory drug treatment prior to the onset of proteinuria .
three patients had progressed to chronic renal failure , but the rate of progression was variable .
one other patient revealed mildly decreased renal function one year after diagnosis with fsgs5 ) .
normal renal function was maintained in the remaining two patients , and , interestingly , proteinuria resolved completely in one of these patients after one year treatment with potassium supplements , spironolactone , and indomethacin3 ) .
the renal pathologic findings were described in detail in three cases , two of which had perihilar type fsgs .
the perihilar variant is common in patients with secondary forms of fsgs mediated by glomerular hyperfiltration or other adaptation after loss of renal mass8 , 16 ) .
these findings suggest that fsgs complicated by bs may be a secondary lesion due to adaptive response to chronic hyperfiltration by chronic salt - loss and resultant chronic stimulation of the renin - angiotensin system .
several case reports of gitelman syndrome complicated by fsgs support this explanation17 , 18 ) .
case reports of patients with bs who underwent renal transplantation are also rare , and the causes of esrd include progression of fsgs or other causes including complication of long - term non - steroidal anti - inflammatory drug treatment6 , 12 - 15 ) . in one of the patients , pre - emptive bilateral native nephrectomies and renal transplantation were conducted prior to the onset of esrd due to severe , clinically brittle , neonatal bs15 ) . in all of the cases ,
transplantation was successful and bs disappeared completely after transplantation as shown in our patient . in summary , bs may be complicated by fsgs due to adaptive response to chronic salt - losing nephropathy , and fsgs may cause esrd in some patients .

Answer:
bartter syndrome ( bs ) is a clinically and genetically heterogeneous inherited renal tube disorder characterized by renal salt wasting , hypokalemic metabolic alkalosis and normotensive hyperreninemic hyperaldosteronism .
 there have been several case reports of bs complicated by focal segmental glomerulosclerosis ( fsgs ) . here
 , we have reported the case of a bs patient who developed fsgs and subsequent end - stage renal disease ( esrd ) and provided a brief literature review .
 the patient presented with classic bs at 3 months of age and developed proteinuria at 7 years .
 renal biopsy performed at 11 years of age revealed a fsgs perihilar variant .
 hemodialysis was initiated at 11 years of age , and kidney transplantation was performed at 16 years of age .
 the post - transplantation course has been uneventful for more than 3 years with complete disappearance of bs without the recurrence of fsgs .
 genetic study revealed a homozygous p.trp(tgg)610stop(tga ) mutation in the clcnkb gene . in summary ,
 bs may be complicated by secondary fsgs due to the adaptive response to chronic salt - losing nephropathy , and fsgs may progress to esrd in some patients .
 renal transplantation in patients with bs and esrd results in complete remission of bs .


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:
reliable information on morbidity and mortality is the key for evidence - based public health practice .
more emphasis on estimating burden of diseases was given at global level , especially since the launch of  global burden of disease study .
 while the decision - making priorities of global health authorities are dependent on these projected data , developing countries often lack the local data for proper public health planning .
health professionals still fights to establish vital registration , while the morbidity surveillance is still in its initial stage . in countries where information is available ,
data from ambulatory care services , primary healthcare centers , and outpatient departments ( opd ) are often lacking .
economic impacts of the mild to moderate ill health conditions are considerable given the large number of patients utilizing these services .
as an example , in sri lanka , more than 43 million visits are made to the opds in government hospitals annually .
given that the only 50% of outpatient care is delivered through public sector , the total outpatient visits are estimated to be more than 80 million , four times the sri lanka population of 20 million . despite this heavy burden , information on opd morbidities are not routinely collected and used in healthcare planning .
as a preliminary study to assess the burden of disease and morbidity pattern in opd , we conducted a rapid survey in a tertiary care hospital in sri lanka .
study sample consisted of opd patients visiting teaching hospital peradeniya , which is the teaching hospital for second largest medical school in sri lanka .
three of the six authors physical presented at the opd during the study period , explained the procedure to patients , and consented patients filled a self - administered short questionnaire .
a half - page questionnaire was used and the main problem which patients sort medical advice was inquired .
a total of 3817 patients attended opd during the study period and 1908 were recruited as the study sample using the systematic sampling strategy .
of them , 1439 completed the questionnaire with a response rate of 75.4% . a significantly higher number of females ( 924,64.2% ) visited the opd compared to males ( 515,35.8% ) ( chi square for goodness of fit 116 , p<0.001 ) .
the age of the patients attending the opd ranged from 1 year to 89 years .
the mean age of the study sample was 40 years ( sd = 19 years ) .
majority of the females attending the opd were of middle age while males were distributed evenly among all age categories .
the mean age of females was significantly higher than that of males ( t = 4.03 , p<0.001 ) .
housewives constituted the major occupational group among females , accounting for 52% of the total sample , followed by adolescents ( 15.9% ) .
ten leading cause of opd visits were nonspecific body aches and pains  225 ( 15.6% ) ; respiratory symptoms ( cough and cold )  151 ( 10.5% ) ; abdominal pain  122 ( 8.5% ) ; fever - 117 ( 8.1 ) ; backache and joint pains  112 ( 7.8 ) ; skin conditions - 106 ( 7.4 ) ; constipation - 84 ( 5.8 ) ; chest pain  66 ( 4.6 ) ; diarrhea - 59 ( 4.1 ) ; and dog bite / s  51 ( 3.5 ) . table 1 shows the leading morbidities according to sociodemographic profile of the patients . among children (  10 years)/school children , cough and cold was the commonest complaint followed by dog bites .
constipation ( 14.5% ) was the commonest presenting complaint among tamils ( 6.3% ) but was not in the leading five commonest complaints among the other ethnic groups .
main presenting symptom among adolescents was various skin conditions , which was third commonest condition among young adults .
commonest presenting complaint by demographic characteristics among patients attending outpatient department of teaching hospital peradeniya , sri lanka ( n = 1 439 )
this could be explained partly from the so - called  male - female health survival paradox
( i.e. , males report better health than females , but encounter higher mortality at all ages ) .
there is growing evidence to conclude that men are healthier , but have substantially higher mortality rates .
however , this could be also due to a gender difference in health - seeking behavior as shown in previous studies.[46 ] children less than 10 years accounted for only 5% of the opd patients , which shows a marked difference from the private sector utilization in sri lanka where 32% of encounters were reported as children , which was completely different from the findings of the present study .
previously , respiratory tract problems were reported as the commonest encounter in government phc setting as well as in gp practice in sri lanka , with higher percentages ranging from 20% to 55%.[79 ] in our study , respiratory problems was the commonest among younger age groups . however , nonspecific body aches and pains was the leading encounter .
however , this problem needs to be studied to provide meaningful services . despite having low annual numbers of rabies
, dog bite showed to be a leading problem among children . reported constipation encounters as leading reason for opd care seeking among tamil ethnic group
these observations from a single hospital could not be generalized to sri lanka or other developing countries .
however , our study provides early evidence for probability of changing morbidity patterns with demographic transitions that should be taken into account in public health program planning .

Answer:
background : global disease burden estimates often lack real data on morbidities , especially from patients treated in outpatient department ( opd ) . in sri lanka , around 40 million visits are made annually to the opds in government hospitals and we conducted a preliminary study to assess the morbidity profile of these opd patients.methods:patients attending the opd , in teaching hospital peradeniya , sri lanka , was recruited into the study using systematic random sampling procedure .
 a self - administered , structured questionnaire was used to collect data .
 investigators explained the study to patients and data collection was completed before seeing the physician .
 self - reported presenting complain was used to analyze the morbidity profile of the patients.results:the study sample consisted of 1 439 patients ( male - 515 , female - 924 ) .
 the mean age of the study sample was 40 years ( sd = 19 years ) .
 the mean age of the females were statistically significantly higher than that of the males ( t = 4.03 , p<0.001 ) .
 housewives constituted the major occupational group ( 52% ) followed by students ( 15.9% ) .
 the most common presenting complains reported were body aches and pains ( 15.6% ) , cough and cold ( 10.5% ) , and abdominal pain ( 8.5% ) .
 leading cause of hospital visit among different demographic categories showed statistically significant variations.conclusions:the morbidity pattern observed in this patient population was not previously reported .
 opd surveillance should be established to understand the changing pattern of minor ailments which might have a huge impact on health of the public .


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:
ovotesticular disorder of sex development ( ot - dsd ) is a rare disorder of sexual
 differentiation characterized by the presence of testicular tissue with distinct
 seminiferous tubules and ovarian tissue with mature ovarian follicles in the same gonad
 ( ovotestis ) or separately in a single individual ( 1 ,
 2 ) . ot - dsd
it constitutes between 3 and 10% of the
 total dsd and presents significant diagnostic and management challenges ( 3 , 4 ) .
typically ,
 both mullerian and wolffian duct derivatives are seen , and most affected individuals
 commonly present with ambiguous external genitalia as neonates or infants .
however , the
 phenotype of the external genitalia may range from normal male to normal female depending on
 the degree of testicular tissue present .
the ovotestis is usually the most common gonad in
 individuals with ot - dsd , and such gonads are known to be at an increased risk of developing
 germ cell tumors ( 5 ) .
more than five hundred cases of ot - dsd including familial cases have been reported in
 medical literature ( 3 , 6 , 7 ) .
epidemiologically , the geographical
 distribution of ot - dsd shows a higher prevalence in the african continent , especially among
 south african blacks , with the number of published cases being 17 per 100 million people ,
 followed by europe at 15.3 .
age and mode of presentation is often variable and
 usually comprises hypospadias , unilateral or bilateral cryptorchidism , inguinal hernia ,
 urogenital sinus , gynecomastia at pubertal age or lower abdominal mass in adulthood ( 4 ) .
internally , the presence of an ovotestis is the most
 common finding followed by ovaries ( 4 , 9 ) .
the chromosomal findings in ot - dsd were first reported in 1959 by hungerford , who
 demonstrated a 46,xx chromosomal complement in peripheral blood lymphocytes of an individual
 with this disorder ( 10 ) . ot - dsd is a genetically
 heterogeneous condition with the predominant karyotype being 46,xx , while 46,xx/46,xy
 chimerism , 46,xy karyotype and x - y translocation are less frequent ( 4 ) .
the objective of this paper is to describe the diverse clinical ,
 cytogenetic and histopathological features of five patients diagnosed with ot - dsd in sri
 lanka .
this is a report of the clinical , cytogenetic and histopathological data of patients with
 ot - dsd who were referred to the human genetics unit for cytogenetic evaluation between 2005
 and 2011 .
this facility serves as the main referral center for cytogenetic testing in sri
 lanka , and the majority of children with dsd in the country undergo karyotype testing at
 this center .
the diagnosis of ot - dsd had been
 confirmed by histopathological examination of the gonads , which were biopsied either
 laparoscopically or at exploratory laparotomy .
five milliliters of peripheral blood was
 obtained from each patient , and chromosomal analysis was performed on routinely cultured
 lymphocytes after gtg - banding .
karyotyping was done according to guidelines of the
 international system for human cytogenetic nomenclature ( iscn , 2005 ) .
at least 30
 well - spread and well - banded metaphases were examined in each patient by an experienced
 cytogeneticist .
the age , sex of
 rearing , mode of presentation , status of the external and internal genitalia and karyotypes
 of the patients are summarized in table
 1 .
their ages ranged from 2 mo to 47 yr , and all were reared as males . in four
 of the patients ( cases 1 , 3 , 4 and 5 ) ,
two
 patients ( cases 1 and 3 ) had perineal hypospadias with bilateral cryptorchidism , while the
 other two patients ( cases 4 and 5 ) , who were siblings , both had male external genitalia with
 a short , blind - ending vagina and bilateral inguinal lumps .
case 2 was reared as a male but
 started feminizing and developed female secondary sexual characteristics at puberty with
 gradual atrophy of both testes .
case 1 underwent surgical correction for perineal
 hypospadias during early childhood but remained undiagnosed until an exploratory laparotomy
 performed for an intra - abdominal lump led to the diagnosis of ot - dsd at the age of 47 yr . in
 addition to the lower abdominal mass , this patient was observed to have gynecomastia .

two patients had
 bilateral ovotestis : one had an ovotestis on one side and an ovary on the other side , the
 other had an ovotestis on one side and a testis on the other side ; the remaining patient had
 an ovary and testis separately on either side .
four patients ( cases 1 , 2 , 4 and 5 ) had a
 46,xy chromosome complement , while 46,xx/46,xy chimerism was observed in the remaining
 patient ( case 3 ) . there were no cases of 46,xx karyotype .

table 1  profiles of the five patients with ovotesticular disorder of sex
 developmentcaseagesex of rearingindication for investigationexternal genitaliainternal genitalia / gonadskaryotype147 yrmaleambiguous genitalia at birth / abdominal
 mass in adulthoodperineal hypospadias , bilateral
 cryptorchidismuterus with tubes , left ovotestis and
 right testis 46,xy223 yrmalefemale secondary sexual characteristics at
 puberty with gynecomastiamale external genitalia with bilateral
 atrophic testes uterus with tubes and bilateral streaky
 ovaries and atrophic testes46,xy32 momaleambiguous genitalia / inguinal lumpperineal hypospadias , bilateral
 cryptorchidismuterus with tubes , left ovary and right
 ovotestis46,xx/ 46,xy49 momaleambiguous genitalia / bilateral inguinal
 lumpsmale external genitalia with blind - ending
 vaginauterus with tubes and bilateral
 ovotestis46,xy55 yrmaleambiguous genitalia / bilateral inguinal
 lumps male external genitalia with blind - ending
 vaginauterus with tubes and bilateral
 ovotestis46,xy

ot - dsd is a rare disorder of sexual differentiation that is phenotypically and genetically
 heterogeneous with wide - ranging manifestations .
the presence of well - differentiated ovarian
 and testicular tissue in the same individual , whether as a single tissue - type gonad or an
 ovotestis , is the hallmark of this condition ( 9 ) .
most
 patients with ot - dsd have ambiguous genitalia and are often diagnosed within the first few
 months to years of life ( 1 , 4 , 9 ) .
in addition to ambiguous
 genitalia , patients may present with inguinal hernias , gynecomastia during adolescence or
 lower abdominal mass in adulthood ( 4 , 11 ) .
four out of 5 patients in this series had ambiguous genitalia
 diagnosed in the first few months to years of life , and all were reared as phenotypic males .

inguinal hernias and gynecomastia were also present in some patients . a small number of
 ot - dsd cases are incidentally picked up during laparotomy for unrelated causes .
one of the
 patients in this series had a similar presentation ; he presented with a lower abdominal mass
 in the fourth decade that was later discovered to be an 18-wk - size uterus at laparotomy . a
 similar case of ot - dsd in a 42 yr old was reported in north india ( 4 ) . in ot - dsd
, the degree of virilization of the external genitalia
 depends on the capacity of the testicular tissue to secrete testosterone .
previous studies
 indicate that although approximately 70% of ot - dsd patients are raised as males , less than
 10% have normal male external genitalia ( 1 ) .
it is
 generally believed that the leydig cell function of the dysgenetic testis is inadequate for
 normal virilization ( 4 ) , and this is exemplified in
 this series by case 2 , who had bilateral atrophic testes and started feminizing at puberty .

previous reports have also indicated that testicular tissue in ot - dsd patients becomes
 dysgenetic and that germ cells begin to disappear with increasing age ( 12 ) .
the patients in this study had internal genital organs ranging from streaky ovaries and a
 uterus to atrophic testes , but the common presenting gonad was the ovotestis .
it is known
 that gonadal tissue may be located at any level along the route of embryonic testicular
 descent and is frequently associated with an inguinal hernia
. a sub - classification of ot - dsd
 based on the type and location of the gonads has been described ( 13 ) . according to this classification , ot - dsd
is considered to be lateral
 if a testis is present on one side and an ovary is present on the other side ( case 2 ) ,
 unilateral if an ovotestis is present on one side and a testis or ovary is present on the
 other side ( cases 1 and 3 ) and bilateral if an ovotestis is present on both sides ( cases 4
 and 5 ) .
( 9 ) reported
 that the ovotestis was the most frequent gonad , accounting for 59% in their series of 16
 patients with ot - dsd , and krob et al .
( 3 ) also reported that an ovotestis was found in 44.4% of 568 gonads examined . the
 same observation is reflected in this series , in which 4 out of 5 cases ( 1 , 3 , 4 and 5 ) had an
 ovotestis and 2 of the patients , who were siblings , had bilateral ot - dsd . with regard to the
 frequency of gonadal distribution
, it is reported that the most common form is ovotestis
 plus ovary followed by bilateral ovotestis and ovary on one side and testis on the other
 side , representing 34% , 29% and 25% of cases , respectively ( 8) .
previous studies have reported that the risk of germ cell tumors , especially
 dysgerminomas , in patients with ot - dsd ranges from 4% among those with the 46,xx karyotype
 to up to 10% in those with 46,xy and 46,xx / xy chimerism ( 4 , 5 ) .
analysis of the chromosomal distribution of ot - dsd shows that about 5065% cases have a
 46,xx chromosomal constitution followed by 46,xx/46,xy chimerism , while less than 10% have a
 46,xy karyotype ( 1 , 8 , 9 ) .
the 46,xy karyotype is believed to be
 extremely rare and equally distributed throughout asia , europe and north america ( 3 ) .
in contrast to published reports ( 3 , 4 , 8 , 9 , 14 ) , the predominant karyotype was 46,xy in 80% of the
 patients in this series . there is no apparent reason for 46,xy being the most common
 karyotype in this study other than the small number of patients studied , with possible
 over - representation of the 46,xy karyotype in this study sample , or it could be reflective
 of the pattern seen in the sri lankan population .
karyotypes such as 46,xx/46,xy , which was
 seen in only one patient , are thought to result from chimerism , possibly from double
 fertilization ( involving two spermatocytes  one x and one y ) of either a binucleate ovum or
 of an ovum and its polar body ( 15 ) . in some of the patients , proper investigation and accurate
diagnosis had been delayed for
 many decades in spite of ambiguous genitalia being detected early in life , which led to
 clinical and psychological problems in their adult life .
it is therefore recommended that in
 addition to cytogenetic evaluation , phenotypic males with ambiguous genitalia should be
 thoroughly investigated by means of either abdominal ultrasound scan and/or exploratory
 laparoscopy / laparotomy with histopathological examination to properly assess the exact
 nature of their internal genital system .
although considered a rare presentation , the cases
 reported in this series suggest that abnormal inguinoscrotal or abdominal masses may occur
 in ot - dsd and should be considered in the differential diagnosis of patients , especially in
 those with cryptorchidism and inguinal hernia having the 46,xy karyotype .

Answer:
ovotesticular disorder of sex development ( ot - dsd ) is a rare disorder of sexual
 differentiation in which the gonads of an individual are characterized by the presence of
 both mature ovarian and testicular tissues .
 the objective of this paper is to report the
 clinical , cytogenetic and histopathological findings in sri lankan patients diagnosed with
 ot - dsd who were referred to the human genetics unit for cytogenetic evaluation during 2005
 to 2011 .
 five patients had histopathologically confirmed ot - dsd .
 their ages at
 presentation ranged from 2 mo to 47 yr .
 clinical symptoms varied from ambiguous genitalia
 and inguinal hernias at birth to a lower abdominal mass presenting in adulthood .
 all 5
 were reared as phenotypic males .
 an ovotestis was detected in all cases except one , and
 the predominant karyotype was 46,xy .
 the findings in this series of predominantly 46,xy
 karyotype are in contrast to previously published reports that have reported 46,xx as
 being the predominant karyotype .
 it is therefore recommended that individuals with
 ambiguous genitalia who have the 46,xy karyotype should be thoroughly investigated by
 ultrasonographic or laparoscopic assessment to determine the exact nature of their
 internal genital organs . ot - dsd
 should also be considered in the differential diagnosis of
 patients with cryptorchidism and inguinal hernia .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
a 21-month - old male patient , 75 cm in height and 10 kg in weight , experienced tricuspid valve regurgitation ( tvr ) and was scheduled to undergo tricuspid valve plasty . the tvr was discovered in a follow - up test 1 year after he had undergone ventricular septal defect repair surgery . before tricuspid valve plasty
, a tee was performed , which showed a level 3 - 4 tvr and severe right ventricular hypertrophy .
atropine , thiopental sodium , and vecuronium were administered to induce anesthesia and muscle relaxation .
a catheter was placed at the left radial artery to measure the constant blood pressure and analyze the abga ( table 1 ) .
there were complications due to the adhesion of the svc and ivc near the surgical site .
therefore , a 20 fr and 22 fr cannula was placed on them , respectively . 2 u of packed red blood cells ( prc ) , albumin , and mannitol was used as the priming solution . immediately after activating the cardiopulmonary bypass , the measured hematocrit level was 27.5% .
the acid - base balance management mid - surgery was performed with an -stat . during extracorporeal circulation ,
the body temperature was aimed at a moderately low degree of 25. the perfusion rate was kept at 0.5 - 1.0 l / min .
after tricuspid valve surgery , the patient was weaned from the cardiopulmonary bypass by reducing the perfusion rate of the machine and starting mechanical ventilation .
the total anesthesia , surgery and extracorporeal circulation time was 510 minutes , 420 minutes and 180 minutes , respectively .
the amount of blood loss was estimated to be 800 ml . during surgery , 600 ml of a crystalloid solution , 3 u prc and 2 u platelets were administered .
however the patient 's eyes could not focus , and his upper and lower limbs experienced intermittent convulsions .
brain computed tomography revealed findings indicative of a cerebral infarction in the occipital lobe ( fig .
eeg was performed , which showed no abnormal findings of alpha rhythm loss , which is customary in cortical blindness .
phenobarbital was administered until 19 days after surgery under the suspicion of a connection between the ocular deviation and the convulsions .
the convulsions did not return , but the reaction to light or objects in front of the eyes did not trigger an avoidance response from the patient .
there were no hopeful clinical signs of a visual recovery but fundoscopy showed normal findings .
on the postoperative day 28 , when the flash visual evoked potential ( fvep ) and mri had been planned , the patient 's eyes refocused .
he was able to recognize the objects in front of his eyes , could walk and avoid things in his path , and was able to recognize his guardians .
post surgery visual loss or reduction can be caused by a variety of factors , and occurs 0.1% to 1% of cases .
visual loss is caused by damage to any connecting striate area between the cornea and occipital cortex .
direct pressure on the eyeball , indirect increase in ocular tension due to improper positioning and blood vessel damage can cause central retinal artery occlusion or ischemic optic nerve damage , which can lead to visual loss . in addition , a severe decrease in blood pressure , emboli , and thrombus mid- or post - surgery can cause an infarction in the occipital cortex , which can lead to cortical blindness .
visual loss after a cpb might be caused primarily due to emboli , severe low blood pressure , acute anemia , hypoxia or a combination of these factors . in the present case
twenty seven cases were cortical blindness , of which 22 cases occurred after cardiac surgery ( 81% ) .
aldrich et al .   reported a retrospective study of 25 patients , where the causes of cortical blindness were natural ischemic stroke in 8 patients ( 32% ) , cardiac surgery in 5 patients ( 20% ) , cerebral angiography in 3 patients ( 12% ) , non - surgery in 4 patients ( 16% ) , seizure in 2 patients ( 8% ) , and other factors , such as damage to the head and peritoneal dialysis , in 3 patients ( 12% ) .
there were also cases of temporary cortical blindness reported after post - cardiac surgery angiography . in the case of children ,
the early indicators of brain damage after surgery are age , the complexity of surgery , metabolic acidosis , increase in lactate , and artery acidosis . diagnosing cortical blindness is simple when the patient makes a complaint but as in our case , a pediatric patient has limited ability to communicate . therefore , conducting an eeg , fvep , angiography , and funduscopy can assist in making a diagnosis . in this case , the eeg did not show the abnormal finding of a loss in alpha rhythm . however , computed laminography revealed an infarction in the occipital cortex
we checked for visual loss with light and objects to test the patient 's avoidance response but he did not respond properly .
however , microemboli caused by extracorporeal circulation can obstruct the blood flow in the cerebral vessels , particularly in the watershed area .
braekken et al .   reported that cardiac surgery using extracorporeal circulation causes microemboli in most cases .
in addition , in patients with neural damage , there are more cases of transcranial doppler detection of microembolic signals in the right middle cerebral artery than in patients without .
microemboli mid - surgery occurs most often when blocking the aorta ( 18% ) and unblocking the aorta ( 13% ) .
rodriguez and belway   stated that in pediatric cardiac surgery , the likelihood of microemboli can increase with increasing time of extracorporeal circulation depending on the oxygenator , circuit , adnexa parts , and components .
the surgery in this case was not complicated , but may have increased the likelihood of microembolization due to the long extracorporeal circulation time .
however , we should have been more careful in the selecting the -stat and ph - stat method .
nevertheless , the strength of the ph - stat should have been considered regarding neural sequelae .
the cpb priming solution in pediatric patients , unlike adults , can cause blood thinning , which can lead to possible ischemic organ failure .
aldrich et al .   reported that conditions , such as the age below 40 , no diabetes or high blood pressure , and no impairment in cognitive skills , language skills or memory , indicate a good prognosis for visual recovery .
in addition , eeg tests can assist in a diagnosis but are not helpful in accurately predicting the prognosis . in this study ,
two weeks after the surgery , he recovered his speech and cognitive skills , so we did expected a good prognosis .
the patient 's vision recovered rapidly from postoperative day 28 and he could be discharged .
other tests such as a fvep were not performed , so the precise extent of the recovery rate is unknown .
considerable effort is required to reduce neural sequelae after pediatric cardiac surgery , such as visual loss .
the cpb machine 's circuit components and type choice should be made on what can best prevent the likelihood of emboli .
a pediatric transesophageal scan and cerebral oxymeter can help in the early identification of neural side - effects .
a transesophageal scan plays an important role in eliminating emboli , so it should be prepared for all suitable pediatric patients .
the pathological difference between an adult and pediatric cardiopulmonary bypass should be recognized , and proper measures should be followed .
when cortical blindness is suspected , the ophthalmologist and neurologist should perform a combined examination , being cautious of permanent sequelae . in conclusion , with the reported visual loss in our pediatric patient , surgeons should consider the possibility of visual loss and cerebrovascular injury after a cardiac surgery using cardiopulmonary bypass .

Answer:
visual loss occurring after pediatric cardiac surgery employing cardiopulmonary bypass ( cpb ) is relatively rare but the risk is substantial .
 compromised cerebral perfusion due to a cpb related micro - embolization and inflammatory vascular changes as well as reduced oxygen carrying capacity in hemodilution and hypothermia during cpb might be major contributing factors to the development of postoperative visual loss after cardiac surgery with cpb .
 a case of immediate but transient postoperative visual loss was encountered in a 21-month - old male who underwent tricuspid valve surgery . despite routine intraoperative measures to maintain an adequate perfusion pressure throughout the procedure , postoperative computed tomography revealed a subacute infarct in his occipital lobe .
 recovery began on postoperative day 28 , and the patient 's vision was restored by 31 days .


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:
on april 21 , 2008 , three whooper swans ( 2 adults and 1 juvenile ) were found dead at lake towada , akita prefecture , japan ( figure 1 ) .
it was taken to the wildlife protection center in akita but had to be euthanized that day in moribund status .
homogenates from the tracheas , cloacas , and internal organs of 3 swans were pooled and inoculated into embryonated chicken eggs for virus isolation .
map of japan and nearby countries , with enlargement of the northern part of the country ( inset ) showing location of lake towada .
agents were confirmed to be type a influenza viruses by a commercial rapid antigen assay kit and were excluded from being newcastle disease virus by the hemagglutination inhibition test with newcastle - specific antiserum .
after those tests conducted at the animal hygiene service center , viruses were brought to the national institute of animal health , tsukuba , japan , for further analysis .
the viruses were subtyped as h5n1 with a panel of antiserum , and 1 yielded from cloaca homogenates was designated as a / whooper swan / akita/1/2008 ( wsak08 ) and was further analyzed .
wsak08 was shown to be highly pathogenic to chickens by an intravenous administration of 10-fold diluted infectious allantoic fluid .
this result coincides with the sequence analysis of the hemagglutinin ( ha ) gene , showing that the ha protein possesses a series of basic amino acids ( pqrerrrkr ) at the cleavage site .
phylogenetic analysis of the ha1 region of the ha gene ( figure 2 ) showed that wsak08 belongs to clade 2.3.2 and is clearly distinguishable from the hpaivs previously isolated in japan in 2004 , a / chicken / yamaguchi/7/2004 ( clade 2.5 ) , and in 2007 , a / chicken / miyazaki / k11/2007 ( clade 2.2 ) . although sequence data were not found in genbank , a / common magpie / hong kong/5052/2007 reportedly resides in the same clade ( 9 ) .
antigenic analysis of wsaki08 with a panel of antiserum and monoclonal antibodies showed low reactivity against antibodies in the panel ( appendix table ) . a > 32-fold reduction from homologous titers of all hyperimmune serum used
postinfection duck serum against a / chicken / yamaguchi/7/2004 and a / chicken / miyazaki / k11/2007 did not react with wsak08 .
none of the monoclonal antibodies against ha protein of a / chicken / yamaguchi/7/2004 reacted with wsak08 .
thus , wsak08 is genetically and antigenically distinguishable from the hpaivs that caused previous outbreaks in japan .
phylogenetic tree constructed based on the hemagglutinin ( ha ) 1 region ( 966 bp ) of the ha gene of the highly pathogenic avian influenza viruses ( h5n1 ) .
clade designation follows the criteria proposed by the world health organization / world organisation for animal health / food and agriculture organization h5n1 evolution working group ( 8) .
representative strains of the previous highly pathogenic avian influenza outbreaks in japan are in boldface .
ab436731ab436738 ) showed that it does not contain amino acid substitutions conferring resistance to adamantane or neuraminidase inhibitors . unlike many isolates related to qinghai lake strains that have spread worldwide
the neuraminidase protein has a 20-aa deletion at aa 49 to 68 in the stalk region .
nonstructural protein 1 has a 5-aa deletion at aa 80 to 84 , commonly observed in currently circulating hpaivs ( h5n1 ) in southeastern asia .
whooper swans breed in northern eurasia and winter in europe and eastern asia i.e. , china , the korean peninsula , and japan . in japan
, 35,00038,000 whooper swans spend every winter primarily in hokkaido , tohoku , and the hokuriku area ( 10 ) . in the lake towada area , 300 whooper swans arrive beginning in late october ; they leave the area between late march and late april ( 11 ) . in late march , summer birds begin to arrive . according to results of satellite tracking of 8 swans ( 12 ) , as well as the results of banding studies since 1961 ( 13 ) ,
whooper swans that winter in japan migrate from the northern end of honshu island to eastern hokkaido , by means of sakhalin , and reach eastern siberia , where they breed . to our knowledge , there have been no reports of whooper swans that winter on the eurasian continent migrating north through japan . in light of the migratory route mentioned above , the whooper swans found dead at lake towada were most likely recently infected with hpaiv ( h5n1 ) in japan .
it is unlikely that the swans were infected before they flew to japan in autumn , maintained the virus within the flock , and then suddenly developed the disease after no apparent infections for several months .
although the susceptibility of a certain species of birds to a subtype h5n1 virus may be different depending on the virus strain ( 14 ) , whooper swans as well as mute swans have been considered to be susceptible species to hpaiv ( h5n1 ) , as they showed a fulminant course of disease at the outbreak in germany in 2006 ( 7 ) .
the possibility that the swans were infected by domestic fowl is low because there has been no report of hpai among domestic fowl in japan since the beginning of 2008 .
one possible explanation is that other wild birds brought the virus from outside the country .
although it is not known whether any birds wintering on the continent migrate north through japan , passage visitor birds such as wader birds migrate from south to north through japan in spring ; summer birds , e.g. , egrets , swallows , songbirds , and some raptors , come to japan from the south in spring for breeding .
also , the possibility of anthropogenic introduction of virus , such as by inappropriate importation of birds , meats , or materials , can not be excluded . in conclusion
, genetic analysis demonstrates that the virus that killed the 4 swans in japan in 2008 is genetically distinguishable from the strains that caused previous poultry outbreaks in japan , ruling out a possibility of resurgence of previously introduced hpaiv in japan . after the incident we describe
, 2 other whooper swan cases of hpaiv ( h5n1 ) infection were confirmed in eastern hokkaido in early may .
possible involvement of wild birds in the introduction of the virus to japan requires further scrutiny .
antigenic analysis of whooper swan / akita/1/2008 highly pathogenic avian influenza virus ( h5n1 ) versus related isolates *

Answer:
on april 21 , 2008 , four whooper swans were found dead at lake towada , akita prefecture , japan .
 highly pathogenic avian influenza virus of the h5n1 subtype was isolated from specimens of the affected birds .
 the hemagglutinin ( ha ) gene of the isolate belongs to clade 2.3.2 in the ha phylogenetic tree .


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:
benign recurrent intrahepatic cholestasis ( bric ) is an autosomal - recessive cholestatic disorder   which was first described by summerskill and walshe in 1959 in two patients with recurring cholestasis [ 2 , 3 ] .
ten years later , tygstrup and jensen   formulated the defining criteria as : ( 1 ) several episodes of pronounced jaundice with severe pruritus separated by symptom - free intervals lasting several months or years , ( 2 ) absence of a factor known to produce intrahepatic cholestasis ( e.g. drug intake , pregnancy , intoxication ) , ( 3 ) biomechanical signs of obstructive jaundice but with normal intrahepatic and extrahepatic bile ducts ( visualized by cholangiography ) , and finally ( 4 ) bile plugs within ducts in histological specimens [ 1 , 2 , 4 , 5 ] .
previously , summerskill - walshe - tygstrup syndrome has been regarded as an idiopathic disease [ 1 , 2 ] .
meanwhile it is known that bric displays a genetic heterogeneity and is associated with mutations in the atp8b1 ( bric 1 ) and abcb11 ( bric 2 ) genes and belongs to the  canalicular transport defects .
as it typically does not lead to liver cirrhosis , it is considered as a benign liver disease .
for the right diagnosis , both clinical and pathological features are pivotal [ 5 , 6 ] .
therapeutically , in moderate cases , conservative treatment with cholestyramine , rifampicin [ 6 , 7 , 8 ] , steroids , phenobarbital , ursodeoxycholic acid or 5-adenosylmethionine   may be applied . in more severe cases , a nasobiliary drainage tube can be inserted , or surgical interventions such as partial biliary diversion or ileal bypass may be performed to relieve the patient 's suffering . despite these various possibilities , in some patients symptoms  mostly pruritus  may still be resistant [ 5 , 9 ] . for such severe cases ,
new therapeutic approaches are required to avoid liver transplantation as the ultimate required therapy . in 1988 , several attempts succeeded in lowering bile acids by plasmapheresis [ 10 , 11 ] .
additionally , since 2001 , albumin dialysis ( molecular adsorbent recirculation system , mars ) has been successfully applied to improve these patients medical condition and to significantly reduce serum bilirubin and bile acid levels [ 8 , 12 , 13 ] . in the case of our patient , the extracorporeal liver assist device prometheus ( fresenius medical care , bad homburg , germany ) , which is frequently used in patients with severe
cholestasis or liver failure as a bridging procedure to transplantation [ 14 , 15 ] , has been applied to resolve therapy - resistant pruritus .
we report a 45-year - old caucasian woman with summerskill - walshe - tygstrup syndrome which was first diagnosed in 1998 . despite extensive conservative therapy with prednisolone ( 510 mg / day ) , ursodeoxycholic acid ( 3  500 mg / day ) and cholestyramine ( 3  4 g / day )
, she suffered from intermittent attacks of cholestatic jaundice , severe pruritus and anxious nervousness . on clinical examination
usually , serum bile acids were elevated at 22.5  2.7 mol / l ( normal
< 6 mol / l ) , while transaminases as well as -glutamyltransferase ( -gt ) and alkaline phosphatase ( ap ) remained at approximately normal values ( < 35
e , cmv , ebv and hsv ) and immunological serology ( ana , ama , anca , sma , sla , lkm , -globulin and igg / igm ) were all negative .
however , both the patient 's grandmother and mother suffered from cholecystolithiasis . in march 2008
ultrasound examination revealed normal liver morphology without signs of obstructive cholestasis ( diameter of the common bile duct 3 mm ) .
additionally , a liver biopsy was performed which demonstrated normal hepatocyte architecture without inflammatory cells or bile plugs within the canaliculi ( fig .
the first 3 dialysis cycles were performed in april 2008 , followed by another 5 cycles in june 2008 , leading to complete recovery and decreasing laboratory parameters . in the following years
, bile acids were lowered significantly by 78% from an average of 22.5  2.7 to 7.3  1.7 mol / l ( p = 0.003 ) . due to cicatrization of the dialysis catheter , a cimino - brescia fistula was finally applied in january 2011 .
we here report a patient with characteristic features of bric , occurring frequently with insistent symptoms . she suffered from intermitting severe pruritus as well as infrequent jaundice .
this disease is remarkable for its discrepancy between a rise in serum bile acids at the onset of each attack and a later rise in total serum bilirubin levels . due to conservative treatment with prednisolone ( 510 mg / day ) , ursodeoxycholic acid ( 3  500 mg / day ) and cholestyramine ( 3  4 g / day ) ,
in contrast , conservative treatment did not have any positive effects on agonizing pruritus . during this stage
, laboratory parameters revealed the typical periodic elevation of total serum bilirubin and bile acids .
however , transaminases , ap and -gt were less affected ( < 35 u / l ) . whenever intractable pruritus appeared , liver dialysis using the prometheus system was performed .
the first cycle was set after worsening of the patient 's condition when a 7 fr nasobiliary drainage tube dislocated in march 2008 . in the following years
, 3 up to 5 cycles of liver dialysis per session were necessary to normalize laboratory parameters and relieve the patient 's suffering .
this range for dialysis sessions is in accordance with other studies describing the application of prometheus in patients with insistent pruritus [ 16 , 17 , 18 ] .
the pathogenesis of cholestatic pruritus is not completely clear . besides bile acids , which apparently seem to play a major role as pruritogens , elevated levels of endogenous opioids and amphiphilic lysophosphatidic acid ( lpa )
in contrast to bile acids , lpa and autotaxin ( the enzyme responsible for the transformation of lysophosphatidylcholine into lpa ) plasma levels were demonstrated to correlate significantly with the severity of patients pruritus .
conservative treatment is based upon this knowledge as e.g. the bile acid sequestrate cholestyramine is recommended as the first - line treatment by easl and aasld .
involvement of the opioid system furthermore allows the application of opioid antagonists   such as naltrexone to resolve pruritus . reported positive effects of the serotonin re - uptake inhibitor sertraline
actually indicate an involvement of the serotonin system . despite these numerous mechanisms by which the pathogenesis of pruritus can already be affected therapeutically to relieve the majority of patients from pruritus , some of them remain resistant to these therapies . as severe pruritus
may lead to reduced quality of life and even to suicide [ 16 , 17 ] , the necessity for an effective therapy becomes obvious .
in these patients , e.g. with primary biliary cirrhosis , liver transplantation may become the ultimate therapeutic option . until now
, several studies have provided evidence for extracorporeal liver support systems , first for mars and later for prometheus , to be an effective and safe therapeutic alternative for patients with cholestatic pruritus [ 8 , 12 , 13 , 16 , 17 ] . with regard to the elimination of albumin - bound molecules such as bilirubin ( strongly albumin - bound ) or bile acids ( less tightly albumin - bound ) , there are slight differences between these two methods .
krisper and stauber   characterized the dialysis performance of prometheus as less selective to albumin - bound molecules and more efficient at the same time as compared to mars . concerning bile acid removal , stadlbauer et al
.   found similar efficiency for both prometheus and mars , while a change in the particular bile acid profile towards hydrophobic bile acids was observed only under prometheus treatment .
besides changes in white blood cell count , no adverse effects have been reported so far [ 18 , 22 ] .
because of its rareness summerskill - walshe - tygstrup syndrome is first considered in the differential diagnosis of cholestasis after many years of extensive investigations .
however , in some cases , prometheus liver dialysis appears to be a beneficial alternative for patients with bric - related symptoms  mainly intractable pruritus

Answer:
summerskill - walshe - tygstrup syndrome is a rare benign chronic liver disease characterized by recurring cholestasis with jaundice and severe pruritus . due to insufficient conservative treatment , liver dialysis by prometheus
 was applied to a 45-year - old female patient with resistant pruritus .
 initially , other possible liver diseases were excluded and the patient was treated symptomatically since the diagnosis of summerskill - walshe - tygstrup was stated in 1998 . as conservative and endoscopic methods progressively failed to relieve the patient 's suffering , prometheus liver dialysis was performed regularly since 2006 at 3-month intervals and successfully led to a decrease in the patient 's symptoms .
 cholestatic liver enzymes and also serum bile acids could be lowered significantly from an average of 22.5  2.7 to 7.3  1.7 mol / l .
 consequently , prometheus liver dialysis may be a beneficial option for patients with benign recurrent intrahepatic cholestasis suffering from therapy - resistant symptoms and may be used as well as other extracorporeal liver support devices which have already been reported to improve cholestatic pruritus .


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:
bidirectional ventricular tachycardia ( bvt ) is defined as a tachycardia showing beat - to - beat alternation in the qrs axis .
the rate is typically between 140 and 180  bpm , with a frontal plane axis varying between 20 and 110. the most common causes of bvt include catecholaminergic polymorphic ventricular tachycardia and cardiac glycoside toxicity .
other previously described etiologies include myocarditis , long qt syndrome type 7 , congenital cardiomyopathies , cardiac tumors , and acute cardiac allograft rejection .
cardiac sarcoidosis is characterized by myocardial inflammation and interstitial fibrosis that can lead to slowed conduction and macro re - entrant arrhythmias .
we report a case of bvt in a patient with cardiac sarcoidosis and briefly discuss the proposed mechanisms underlying bvt .
a 73-year - old man with history of chronic pulmonary sarcoidosis was seen for an annual checkup , during which ventricular bigeminy was identified on a 12-lead electrocardiogram .
subsequent holter monitor assessment showed multiple premature ventricular beats and several short runs of non - sustained ventricular tachycardia ( vt ) , with two different qrs morphologies ( fig .
1 ) . a cardiac magnetic resonance tomography with delayed gadolinium showed a curvilinear region of patchy mid - myocardial enhancement within the inferolateral left ventricular myocardium near the base , consistent with cardiac sarcoidosis ( fig .
2 ) . the left and right ventricular ejection fractions were 47% and 37% , respectively .
a nuclear myocardial perfusion study using single - photon emission computed tomography showed no myocardial perfusion defects on stress or rest imaging , ruling out ischemia .
a fasting 18-fluorodeoxyglucose positron emission tomography ( pet ) demonstrated increased uptake in the same area of the myocardium that had shown late gadolinium enhancement , consistent with active cardiac sarcoid ( fig .
the patient was elected to have an implantable cardioverter defibrillator ( icd ) placed for prevention of sudden cardiac death .
he had not experienced any vt episodes during the one - year follow - up .
one of the proposed mechanisms of bvt include elevated intracellular calcium , causing delay after depolarization in anatomically separate parts of the conducting system .
proposed that two separate foci , with different rate thresholds for delayed after depolarization  induced ventricular bigeminy , were present in a rabbit model .
this would effectively double the heart rate , increasing the overall ventricular rate above the second threshold .
once this had developed , the two competing sites would simply alternate on a beat - to - beat basis .
this is likely the mechanism underlying bvt observed with digitalis toxicity and catecholaminergic polymorphic vt .
the other proposed mechanisms for bvt include an alternating bundle branch block related to bifocal automaticity and inscribed in opposite directions , or scar - mediated reentry around a circuit with two alternating exit sites .
described a mechanism including retrograde conduction over the mid septal fascicular pathway , with alternating block in the left anterior or posterior fascicles , to explain polymorphic fascicular vt patterns .
scarring is typically patchy , with a predilection for the basal septum , anterior wall , and perivalvular regions of the left ventricle .
it may also be confluent , affecting the right ventricular epicardium or endocardium . in sarcoidosis , it is plausible that multiform or bidirectional premature ventricular contractions ( pvcs ) are due to multiple exits from the areas of inflammation and/or scarring .
conduction disturbances in cardiac sarcoidosis are not uncommon , and often affect the his - purkinje system . in our case ,
the patient had an intraventricular conduction delay at baseline , with prolonged qrs complexes at relatively low atrial rates ( fig .
the majority of the retrospective data suggest that immunosuppression reduces the burden of arrhythmias , especially in the early phases of the disease .
previous case series have reported various success rates with vt ablation in patients with cardiac sarcoidosis , likely due to the small number of patients in each series , with varying degrees of disease burden .
the most common circuit for vt in one report was reentry in the peritricuspid area , which can be safely ablated . in another study , abolishing all inducible tachycardias was not always feasible because of septal intramural circuits , extensive right ventricular scarring , or sites of origin in close proximity to the left anterior descending , the ramus intermedius arteries , or the para - hisian region , which prohibit safe ablation . in the current case , it is likely that the presence of a septal focus leads to alternate exits into the right or left ventricle which shows the observed electrocardiogram pattern .
although the septal involvement was not visible by imaging until a year after diagnosis , it might have been present initially , but was microscopic in nature .
this is consistent with previous autopsy studies that have shown a heterogeneous distribution of sarcoid granulomas in the myocardium .
the recent expert consensus document is an excellent resource for management and risk stratification for cardiac sarcoidosis patients .
icd implantation for primary prevention is commonly performed due to the high burden of vt events ( estimated incidence rate of 15% per year ) in patients with cardiac sarcoidosis . in the current case ,
icd implantation was recommended due to the high burden of nonsustained vt episodes , left and right ventricular dysfunction , and the presence of fibrosis and active inflammation by imaging studies .

Answer:
a 73-year - old man with history of pulmonary sarcoidosis was found to have runs of non - sustained bidirectional ventricular tachycardia ( bvt ) with two different qrs morphologies on a holter monitor .
 cardiac magnetic resonance delayed gadolinium imaging revealed a region of patchy mid - myocardial enhancement within the left ventricular basal inferolateral myocardium .
 an 18-fluorodeoxyglucose positron emission tomography ( fdg - pet ) showed increased uptake in the same area , consistent with active sarcoid , with no septal involvement .
 follow - up fdg - pet one year later showed disease progression with new septal involvement .
 cardiac sarcoidosis , characterized by myocardial inflammation and interstitial fibrosis that can lead to conduction system disturbance and macro re - entrant arrhythmias , should be considered in differential diagnosis of bvt .
 bvt may indicate septal involvement with sarcoidosis before the lesions are large enough to be detected radiologically .


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:
it is estimated to be the most common cause of neonatal hospital readmission in north america ( 1 ) .
it may lead to bilirubin accumulation in basal ganglia and brain stem nuclei and lead to kernicterus .
if the infants survive the acute phase , which is marked by lethargy , hypotonia , poor feeding and opisthotonus , they may develop chronic encephalopathy .
this condition is manifested by cerebral palsy , sensory neural hearing loss , dental dysplasia , upward gaze paralysis and mental retardation ( 2 ) .

causes of severe neonatal hyperbilirubinemia are categorized either as hemolytic ( blood group mismatch , sepsis , g6pd deficiency ) or non - hemolytic ( breast feeding jaundice , internal hemorrhage , gestational diabetes , pyloric stenosis , hypothyroidism and some mutations in hepatic enzymes ) .
prematurity , jaundice in the first 24 hours of life , jaundice noted before discharge from hospital , a history of jaundice treated with phototherapy in siblings and asian race are other predisposing factors for severe hyperbilirubinemia noted by various studies ( 3 - 5 ) .

however , severe hyperbilirubinemia is mainly treated by exchange transfusion ( et).according to american academy of pediatrics ( aap ) , neonates with weight  2500 grams in healthy term , et is indicated when indirect bilirubin level reaches 25 mg / dl and 20 mg / dl and in cases with risk factors or gestational age of35 - 37 wk and well despite 6 hr of intensive phototherapy . in newborns of 35 - 37 wk and risk factors , et is indicated when the indirect bilirubin level reaches  18 mg / dl despite 6 hr of intensive phototherapy ( 2 ) .
et is associated with many complications such as hypersensitivity reactions , sepsis , catheter - induced vascular damage , hypotension , necrotizing enterocolitis , etc ( 5 ) .

the present study has been conducted to investigate the causes of severe hyperbilirubinemia leading to exchange transfusion from march 2009 to march 2011 in bahrami children hospital , tehran , iran .
the aim was to identify neonatal predisposing factors that can be prevented by screening or other measures , thus reducing the incidence of kernicterus , which can be prevented and also to avoid et and its side effects .

 all infants below 30 days who underwent et for severe hyperbilirubinemia in bahrami children hospital during 2009 - 2011 were enrolled into this cross sectional study . a questionnaire prepared consisted of neonates gender , gestational age , age at the time of admission , birth weight , time of jaundice appearance , history of severe hyperbilirubinemia in siblings , blood group and rh of both mother and neonate , g6pd activity , complete blood count , reticulocyte count , peripheral blood smear , total and direct bilirubin before and after exchange transfusion , direct coombs in mother and indirect coombs in neonates , times of transfusion , any other diagnostic laboratory data based on attending neonatologist 's decision and the cause of hyperbilirubinemia stated by the attending neonatologist .
criteria for diagnosis of abo incompatibility were type o maternal blood group and a , b or ab neonatal blood group associated with neonatal hb drop .
positive coombs , peripheral blood spherocytosis and high corrected reticulocyte count were other diagnostic criteria .
icteric breastfed newborns with the beginning of jaundice in the second or third day of life and 2% or more weight loss per day of life with or without uremia or hypernatremia were considered breastfeeding jaundice .

 during the study period , 94 neonates ( 56.4% boys and 43.6% girls ) underwent exchange transfusion due to severe hyperbilirubinemia .
the infants had a mean birth weight of 195040 g and a mean gestational age of 35.21.4 weeks .
fifty nine ( 63% ) of neonates were preterm , and history of neonatal jaundice in siblings was reported in 50% of cases .
however , only 18(19% ) had a history of severe hyperbilirubinemia leading to et in their siblings .

most cases ( 40.5% ) of severe hyperbilirubinmia started to become icteric on the second day after birth .

first day jaundice was observed in 10 neonates , all of them due to hemolysis .
table 1 shows a summary of underlying factors for severe hyperbilirubinemia according to the onset of jaundice .

the majority of infants ( 91.5% ) had only one episode of et , and hemolysis was the sole underlying reason in the remaining who had 2 or 3 episodes of et .
totally , after prematurity , the second most prevalent underlying factor for severe hyperbilirubinemia was breastfeeding jaundice that included 33(35% ) of neonates .
we found that the next most prevalent causes were abo mismatch and g6pd deficiency ( table 2 ) .
there was no kriglernajar cases in our study because no significant hyperbilirubinemia was found after discharging and fallow up .

 according to epidemiological studies , some risk factors are associated with severe hyperbilirubinemia in neonates .
the risk factors are male gender , jaundice presenting in the first 24 hours after birth , jaundice noted at discharge from the hospital , previous sibling with jaundice , preterm labor , breast feeding , rh and abo incompatibility , g6pd deficiency and sepsis ( 4,6 ) .

 according to the canadian pediatric society
, gestational age of 35 - 36 weeks is an important risk factor for hyperbilirubinemia ( 7 ) .
kuzniewicz et al also reported gestational age to be the main predictor of severe hyperbilirubinemia ( 8) . in our series , infants had a mean gestational age of 35.2 weeks and fifty nine ( 63% ) of neonates were preterm .

most cases ( 40.5% ) of severe hyperbilirubinmia started on the second day after birth .
this corresponds with views of american academy of pediatrics and canadian pediatric society , which recommend clinical assessment of infants for jaundice within the first 48 hours of birth ( 6 , 7 ) . however , clinical assessment of newborns is not an accurate means of assessing the severity of hyperbilirubinemia ( 1 ) .

 in the present study ,
breastfeeding jaundice , as the most important factor associated with severe hyperbilirubinemia and according to salas and mazzi ( 9 ) , is encountered in 33(35% ) of cases .
the data also corresponds with findings of huang et al ( 6 ) , who reported an odds ratio of 3.2 for severe hyperbilirubinemia in neonates who were breastfed ( 10 ) .
guidelines advise mothers to nurse their infants at least 8 to 12 times per day for the first several days , rooming in with night feeding , discouraging 5% dextrose or water supplementation and ongoing lactation support for reducing the incidence of breast feeding jaundice ( 2 ) .

 in this study ,
abo mismatch was the third most common cause of severe hyperbilirubinemia and accounted for 24.5% of cases .
this is similar to the reports of badee and sanpavat who reported abo mismatch in 22% and 21.3% of cases , respectively ( 11 , 12 ) .
however , according to canadian surveillance program , the most common causes of severe hyperbilirubinemia were incompatibility abo blood group and g6pd deficiency .

the g6pd deficiency was the fourth most prevalent risk factor for severe hyperbilirubinemia leading to et and accounted for 12(12.8% ) of cases .
badee also reported g6pd deficiency in 19.1% of neonates who underwent et ( 11 ) . according to johnson
et al , g6pd deficiency was considered to be the main cause of hyperbilirubinemia in 19 of 61 ( 31.5% ) infants who developed kernicterus ( 14 ) .

sepsis was the most common underlying cause for et in the study performed by koosha and rafizadeh ( 15 ) .

 prematurity was the most prevalent risk factor for severe hyperbilirubinemia . thus following protocols for prevention of premature labor
is recommended . educating mothers for breast feeding in regard to the right times and method of feeding are important issue that should be considered . since blood group mismatch and g6pd deficiency
were the third and fourth most prevalent underlying factors , screening infants for blood group and if proven to be cost effective , g6pd activity in the first day of life are also recommended . arranging earlier and continuous visits in neonates with these risk factors during the first four days of life are also mandatory .

Answer:
background : severe neonatal hyperbilirubinemia is associated with significant morbidity and mortality .
 this study was conducted to investigate the causes of severe hyperbilirubinemia leading to exchange transfusion ( et ) from march 2009 to march 2011 in bahrami children hospital , tehran , iran in order to establish guidelines to prevent profound jaundice & et .

 methods : 94 neonates underwent et for severe hyperbilirubinemia data for demographic data , and onset of jaundice , history of severe hyperbilirubinemia in siblings , blood group of both mother and neonate , g6pd activity , hemoglobin , hematocrite , reticulocyte count , peripheral blood smear , total and direct bilirubin before and after et , direct and indirect coombs , times of transfusion and the cause of hyperbilirubinemia were all recorded for analysis .

 results : ninety four neonates ( 56.4% boys and 43.6% girls ) underwent et with a mean birth weight of 195040 g and a mean gestational age of 35.21.4 weeks .
 premature labor , breastfeeding jaundice , abo incompatibility and g6pdd with the frequency of 59(63% ) , 33(35% ) , 25(24/5% ) and 12(12.8% ) were of major causes of et .

 conclusions : predisposing factors for severe hyperbilirubinemia in this study were premature labor , breastfeeding jaundice , abo incompatibility and g6pdd . the authors recommend prevention of premature labor , reevaluation of successful breastfeeding education for mothers and screening infants for blood group and g6pd in the first of life . arranging earlier and continuous visits in neonates with these risk factors during the first four
 days of life is also recommended .


Question:
You will be presented with the full text of a biomedical research paper. Please write an abstract for this paper. Your response should include the abstract and no additional text.

Paper text:
an adrenal incidentaloma is an adrenal mass , larger than 1  cm in diameter , detected on imaging studies performed for other indications than adrenal disease [ 1 , 2 ] .
the increasing use of computed tomography ( ct ) scans and magnetic resonance imaging ( mri ) causes a marked increase in incidence of adrenal incidentalomas . in approximately 6% of all autopsies and 4% of all abdominal
ct scans an incidentaloma of the adrenal gland is discovered [ 4 , 5 ] . the incidence of adrenal incidentaloma increases with age to an incidence of 10% in patients over 70 years old .
adrenal incidentalomas are characterized by size , growth , imaging characteristics , and functional status .
although rare , the normal function of the adrenal gland can be disrupted by adrenal incidentalomas . in most cases adrenal incidentalomas will be a small , nonhormonal active cortical adenoma , a benign impediment ( 80% ) .
some adrenal incidentalomas cause hormonal hypersecretion ( 15% ) or appear to be a primary or secondary malignancy ( < 5% ) [ 6 , 7 ] .
adrenal incidentalomas can cause disease by hypersecretion of hormones . conditions due to hormonal activity of adrenal incidentaloma include hypercortisolism , ( cushing 's syndrome ) , catecholamine excess ( pheochromocytoma ) , or hyperaldosteronism ( conn 's syndrome ) .
subclinical autonomous cortisol hypersecretion is the most frequent hormonal abnormality in patients with adrenal incidentalomas .
some of these patients eventually develop overt clinical cushing 's syndrome .   adrenal cortical adenomas with or without hormonal overproduction
vascular lesions of the adrenal are suggestive of a medullary derived pheochromocytoma , but confirmation of a pheochromocytoma by serum or urine measurement of metanephrines is required to diagnose pheochromocytoma .
not only will the radiologist appoint this finding in the radiology report , the radiologist will often also add a recommendation for the next diagnostic procedure .
this retrospective study aims to get a clear view on the detection rate of adrenal incidentalomas on abdominal ct scans in our hospital , and the subsequent diagnostic procedures used after detection of this incidental finding .
this retrospective study was designed to investigate the detection rate of adrenal incidentalomas on abdominal ct scans . for inclusion in this investigation ,
an adrenal incidentaloma was defined as an adrenal mass , greater than 1  cm in diameter , initially discovered by diagnostic imaging for a clinical condition not related to , or suspicious for , adrenal disease .
two investigators learned from an expert radiologist to examine ct scans of the abdomen for primarily the adrenal gland .
each investigator independently evaluated 180 ct scans out of 360 ct scans , of many patients , that were indicated for diagnostics of hepatic , pancreatic , or renal pathology between 2005 and 2007 .
age , gender , indication for ct scan , and abnormalities in size or morphology , were noted .   at the time of examining the adrenal glands ,
the investigators were not aware of the content of ct scans ' radiology report or indication for ct scan . only after their own judgement about size and aspect of the adrenal glands , indication for ct scan and the radiology report
an expert abdominal radiologist ( over 45,000 abdominal ct scans examined ) reviewed the ct scans marked by the investigators with abnormal adrenal glands in size or morphology and results were compared .
if an adrenal incidentaloma was mentioned in the original radiology report , the patients ' record was reviewed to determine whether additional investigations , for example , hormonal studies , additional imaging , or interventional diagnostic studies , were performed after the ct .
an interobserver test was performed to evaluate the resemblance of the way of evaluation between the investigators and expert radiologist .
the ct scans performed for suspected hepatic , pancreatic , or renal pathology of 75 new patients , between 2007 and 2008 , were evaluated for this purpose .
the interobserver variability was calculated with the friedman test , a non - parametric test for coupled observations , with independent observers .
of the 360 patients studied , 206 ( 57% ) were men and 154 ( 43% ) were women .
of the total of 360 patients , 4 patients were excluded because suspected adrenal pathology was also an indication for imaging in these patients . in the remaining 356 ct scans evaluated , the investigators discovered independently a total of 44 ( 12% ) abnormal adrenal glands in 42 patients ( 2 bilateral adrenal incidentalomas ) .
each radiology report was checked for adrenal incidentalomas which were already noted . in 25 ( 7% ) of 356 patients an adrenal mass
the expert radiologist reassessed the ct scans of 42 patients ; the radiologist discovered 17 patients with an adrenal incidentaloma .
two patients had bilateral incidentalomas , giving a total of 19 adrenal incidentalomas not noted previously ( figure 1 ) .
the total number of adrenal incidentalomas was 44/356 ( 12% ) in 42 patients .

figure 3 shows an enlarged right adrenal not mentioned in the initial radiology report . in 64 of 356 ( 18% ) patients , a malignancy was the indication for imaging .
patients with an adrenal incidentaloma were more likely to have a malignancy as indication for ct scan , 20/42 ( 48% ) .
the 25 patients that had an adrenal incidentaloma mentioned in the initial radiology report were checked for additional diagnostic procedures performed . in 3/25 patients a follow - up ct scan
none of these patients showed hormonal overproduction caused by the adrenal lesion . in 2 patients ( 8% ) a second ct scan was performed to exclude increase in adrenal size ; there was no growth of the adrenal lesion shown .
one patient who underwent a hemihepatectomy had a simultaneous resection of the right adrenal incidentaloma .
the interobserver variation was calculated using a friedman analysis test to exclude or to demonstrate a significant difference in perception between different readers .
the friedman test showed that there was no statistically significant difference in perception between the investigators and the radiologist ( p = .867 ) .
the detection of adrenal incidentalomas in this study was 7% and the actual incidence of adrenal abnormalities was 12% after focused assessment of ct scans .
this is high compared to other studies and can be explained by the relatively large group of patients who underwent imaging examination because of a malignancy [ 7 , 11 ] .
however , because of the absence of histological examination of the enlarged adrenal glands , it can not simply be concluded that these patients had metastases in the adrenal gland .
the incidence of adrenal incidentalomas in the literature varies from 0.5% to 15% and depends mainly on the age of the investigated group [ 11 , 12 ] .
only 6 of 25 ( 24% ) patients with an adrenal incidentaloma were further investigated with hormonal workup or imaging .
one reason for the lack of additional diagnostic testing and treatment after detection of an adrenal incidentaloma is the lack of a clear evidence based guideline .
also unfamiliarity with adrenal incidentalomas by the physician who has requested the ct scan will cause lack of additional screening .
another reason for the lack of additional diagnostic testing of adrenal incidentalomas is the apparent lack of direct clinical consequences [ 13 , 14 ] .
undetected hormonal hypersecretion will probably reveal itself in time and the chance of an adrenal carcinoma is low with 0.72/million / year [ 10 , 13 ] . because of this low risk of malignancy and because of the limited impact of hormonal overproduction in an asymptomatic patient , it is not clear whether a guideline for diagnosis and treatment of adrenal incidentaloma is necessary .
such a guideline may cause an increase in diagnostic procedures with additional burden and uncertainty for the patient .
a comprehensive cost - effectiveness study showed however that hormonal analysis of an adrenal incidentaloma is cost effective .
the cost effectiveness of additional imaging of the adrenal gland is less clear in this study .
in addition , the radiation dose to the patient becomes more important and therefore complementary imaging with an mri scan has its advantage .
the optimal strategy for screening and followup of an adrenal incidentaloma is still under discussion .
the guideline of the nih ( 2002 ) seems to be the best alternative in this debate , but the nih already recognized that the guideline is not based on hard evidence .
( table 1 ) protocols on the diagnostic procedures of adrenal incidentalomas are described in several other publications as well , without describing additional prospective data on the clinical results of these protocols [ 9 , 10 , 1518 ] .
there are currently no prospective studies that have examined the effects of an additional diagnostic procedure for adrenal incidentalomas .
following this study a guideline for additional screening and followup was made ( figure 2 ) . in each radiology report a recommendation will be added for every patient with an adrenal incidentaloma and the referring physician is pointed to a webpage with a brief summary about adrenal incidentalomas .
this website also contains the brochure with information for patients , which can be printed .   in conclusion ,
it is not always noted by the radiologist and focused assessment of abdominal cts increased the detection rate of this abnormality form 7% to 12% . when detected and mentioned in the radiologist 's report , only a small percentage of patients receives additional hormonal or imaging investigations to determine the nature of the incidentaloma .

Answer:
objectives . the aim of this study was to investigate the detection rate of adrenal incidentalomas and subsequent workup . design .
 retrospective cohort study . methods .
 two investigators evaluated the adrenals on abdominal ct scans .
 abnormalities were compared to the original radiology reports and an experienced abdominal radiologist reviewed the ct scans . all additional imaging and laboratory tests were assessed .
 results .
 the investigators detected 44/356 adrenal incidentalomas ( 12% ) . in 25 patients
 an adrenal incidentaloma had been noted in the radiology report .
 the expert radiologist agreed on 19 incidentalomas in 17 patients , two with bilateral incidentalomas .
 of the 25 incidentaloma patients , 4 ( 16% ) patients were screened for hormonal overproduction and 2 ( 8% ) patients had follow - up imaging studies .
 conclusions .
 12% of the patients had an adrenal incidentaloma ( 42 of 356 ) .
 17 ( 40% ) had initially not been reported by the radiologist .
 when diagnosed with an adrenal incidentaloma , only a small percentage of patients ( 16% ) is screened or undergoes repeated imaging ( 8% ) as proposed in the national institutes of health ( nih ) guidelines on adrenal incidentalomas .