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:
Genetic variation of fifteen folate metabolic pathway associated gene loci and the risk of incident head and neck carcinoma: The Women\xe2\x80\x99s Genome Health Study

Paper sections:
Introduction

Head and neck carcinoma (HNC), the fifth most common cancer worldwide, is one of the most challenging conditions in clinical oncology owing to its resistance to therapy and high capacity to re-populate during treatment, thus posing a serious public health burden (1, 2). In addition to the well-reported risk factors, including advanced age, alcohol abuse and tobacco use, folate deficiency --an essential (antioxidant) vitamin that is present in fruit and vegetables-- has recently been associated with an increased risk of HNC (3–7). Altered folate metabolism contributes to carcinogenesis via mechanisms that impair DNA synthesis, replication, repair and methylation (7–9). Whether the importance of folate metabolism/deficiency in the underlying pathogenesis of HNC was modulated by genetic variation within the folate metabolic pathway (FMP) associated genes remains elusive (1, 2, 10).

To date, data from large prospective, epidemiological studies on examining the relevance of FMP associated genes as potential risk markers for HNC are scarce. We, therefore, examined the potential involvement of 203 tag-single nucleotide polymorphisms (tSNPs) in fifteen FMP genes (Supplementary Data Tables I and II) with (i) baseline plasma homocysteine (hcys) levels, and (ii) incident HNC, in a large prospective cohort of 23,294 initially healthy US Caucasian middle-aged women.

Study design

Details of the study design have been previously described (11). In brief, participants in the Women's Genome Health Study (WGHS) –a genetic substudy of the Women's Health Study (12, 13)– included initially healthy North American women aged 45 or older with no previous history of cardiovascular disease, cancer, or other major chronic illnesses. A baseline blood sample was collected during the enrollment phase of the Women's Health Study between 1992 and 1995. Study participants, who gave an informed consent for blood-based analyses related to risks of incident chronic diseases, were followed up for incident events that were adjudicated by an endpoints committee using standardized criteria and full medical record review (12, 13). The present investigation included 23,294 Caucasian participants of the WGHS; all were free of known cardiovascular disease and cancer at baseline. During a 15-year follow-up period, 55 cases of newly diagnosed HNC were identified. As described elsewhere, DNA extracted from the baseline WGHS blood samples underwent tSNP (r2 ≈ 0.80) genotyping using the genome-wide Illumina Infinium II Human HAP300 Duo "+" platform (14, 15). The Brigham and Women's Hospital Institutional Review Board for Human Subjects Research approved the study protocol.

Statistical analysis

Genotype frequencies were compared with values predicted by Hardy–Weinberg equilibrium using the chi-square test with one degree of freedom. Multivariable linear regression analysis, adjusting for age, and smoking status, was performed to assess the relationship of the tSNPs with baseline loge-transformed plasma homocysteine (lnhcys) levels. Hazard ratios (HRs) for association of each of the tSNPs with HNC were calculated separately by Cox regression analysis adjusting for age, smoking status, randomized treatment assignment, and further adjusting for baseline lnhcys levels and daily alcohol intake, assuming an additive model for genetic effects.

Haplotype estimation and inference were determined by expectation-maximization algorithm. Haplotype blocks were defined using the software Haploview v4.1. In addition, the relationship between haplotypes and HNC risk was examined by a referent (wild-homozygous) haplotype-based Cox regression analysis, adjusting for the same potential confounders/risk factors used in the single-SNP analysis. Only genes with 3 or more significant tSNPs (arbitrary cutoff) in the single-SNP analysis were further considered for a haplotype-based analysis. All analyses were carried out using SAS v9.1 package (SAS Institute Inc). A 2-tailed uncorrected p-value of 0.05 was considered a statistically significant result. Genotyping call rates were >99% per SNP.

Results

The baseline characteristics of the 23,294 initially healthy Caucasian women are shown in Table 1. Thirty-two out of the 203 SNPs evaluated were not in Hardy–Weinberg equilibrium with uncorrected p-values <0.0500 (Supplementary Data Table I). In the multivariable linear regression analysis, a total of 42 SNPs (22 MTHFR, 8 MTR, 1 RFC1, 4 DHFR, 3 MTRR, 1 MTHFD1, and 3 TCN2) were differentially associated with baseline lnhcys levels (p-uncorrected <0.050; Supplementary data Table III). Results from the multivariable Cox regression analysis showed evidence for differential associations of 11 SNPs (1 MTHFR, 7 RFC1, 1 DHFR, and 2 TYMS) with HNC risk (p-uncorrected <0.050; Table 2). Supplementary Data Table IV presents the nominal (uncorrected) Cox regression results for all 203 SNPs evaluated. Further adjustment for baseline lnhcys levels, and alcohol intake showed virtually identical results (data not shown). Supplementary Data Figure I presents the linkage disequilibrium (LD) pattern of the tSNPs of RFC1 in the present sample population. The haplotype distribution (defined by Haploview v4.1) is shown in Table 3. Results from the haplotype-based analysis again showed an association of two Haploview-defined haplotypes of RFC1 with HNC risk (p-uncorrected <0.050; Table 3), consistent with the involvement of rs10033019. All SNPs evaluated were in agreement of proportionality hazard assumption.

Discussion

To the best of our knowledge, the present prospective investigation is the first to examine the possible involvement of FMP genes in the risk of incident HNC, and we found -suggestive- evidence for an association of the genes evaluated, in particular, the replication factor C-1 (RFC1) gene locus.

Genetic variation within the FMP gene loci has been implicated in various forms of cancer including HNC (1). The FMP genes evaluated in the present study encode proteins for the complex one-carbon interconversion processes, which ultimately regulate and maintain genomic stability. Recent studies have demonstrated the effects of genetic variation within the FMP associated genes, in particular, MTHFR (C677T/rs1801133, A1298C/rs1801131, G1793A/rs2274976), MTR (A2756G/rs1805087), MTRR (A66G/rs1801394, C524T/rs1532268), SLC19A1 (A80G/rs1051266) in modulating risk of HNC (reviewed by Galbiatti and coauthors (1)). However, the present study found no association of the abovementioned gene variants with HNC risk (Supplementary Data Table III). Moreover, the present study confirmed an inverse relationship of MTR A2756G (rs1805087) (16–19), MTRR A66G (rs1801394) (20) with plasma hcys levels, and a null association of MTHFD1 G1958A (rs2236225) with HNC (21), as previously reported.

The present investigation, moreover, suggests that the replication factor C-1 (RFC1) gene variation may play a role in the underlying pathogenesis of HNC. Replication factor C (RFC) is an important factor involved in DNA replication, repair mechanisms, post-translational methylation as well as cell proliferation. Recent experimental investigation of the subunit 1 of Arabidopsis RFC (AtRFC1) -a homologue of p140, the large subunit of human RFC1- showed that AtRFC1 mutations caused defects in embryogenesis and led to embryo and seed abortion (22), suggesting that RFC1 may play a similar role in embryogenesis in humans, and its relevance to the congenital malformations caused by folate deficiency. Furthermore, using interaction cloning, Uchiumi et al. showed that the large subunit of replication factor C interacts with the DNA sequence repeats of telomeres and recognizes the 5-prime-phosphate termini of double-stranded telomeric repeats, thus suggesting that replication factor C may also play a role in telomere stability or turnover (23). Telomere instability, a hallmark of tumourogenesis, is widely demonstrated to play an important role in cancer development (24–26). Owing to the observed functional characteristics of RFC in relation to embryonic development (its relevance to congenital malformations due to folate deficiency), and telomere stability, the present findings encourage the need of further investigation into the possible involvement of replication factor C cascade, and the telomere-telomerase complex in the pathogenesis of HNC.

Strengths of the present study are the overall sample size, the prospective design and the complete long-term follow-up. Nonetheless, some potential limitations of our study require discussion. Our sample population was limited to Caucasian female healthcare professionals from the US. Thus, our results may not be generalizable to other racial/ethnic or socio-economic groups, geographical regions, or to males. Cautious interpretation of our present (uncorrected) findings should be exercised, and confirmation in other prospective studies is needed. Furthermore, pre-cancerous prediction of head and neck carcinoma based on SNPs analysis may be inadequate or low for clinical use (27).

In our study, we had the ability to detect, based on the present sample size, assuming 80% power, at an alpha of 0.05, an effect estimate of greater than 1.65 if the minor allele frequency is 0.50, and of greater than 3.50 if the minor allele frequency is 0.02, assuming a univariable-additive model. Thus, the present study may not have the power to detect a true low-to-modest risk of HNC associated with the gene variants tested.

In conclusion, if corroborated by other large, prospective investigations, the present data from a large cohort of apparently healthy Caucasian US females provide evidence for an association between the folate metabolic pathway associated gene variants tested, in particular, the replication factor C-1 gene locus and the risk of head and neck carcinoma.

Answer: Objective Recent studies have demonstrated the importance of folate metabolic pathway (FMP) in the pathogenesis of head and neck cancinoma (HNC). Whether the genetic variation within the FMP associated genes modulates HNC remains elusive. To date, prospective, epidemiological data on the relationship of FMP gene variation with the risk of HNC are sparse. Methods The association between 203 tag-SNPs (tSNPs) of 15 FMP associated genes (CBS, BHMT, DHFR, FOLR1, FOLR2, FOLR3, MTHFR, MTR, MTRR, MTHFD1, RFC1, SHMT1, SLC19A1, TCN2, and TYMS) and incident HNC was investigated in 23,294 Caucasian female participants of the prospective Women\xe2\x80\x99s Genome Health Study. All were free of known cancer at baseline. During a 15-year follow-up period, 55 participants developed a first ever HNC. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and HNC risk assuming an additive genetic model. Haplotype-block analysis was also performed. Results A total of 11 tSNPs within DHFR, MTHFR, RFC1, and TYMS were associated with HNC risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis revealed an association of several prespecified haplotypes of RFC1 with HNC risk (all p-uncorrected <0.050). Conclusion If corroborated in other large prospective studies, the present findings suggest that genetic variation within the folate metabolic pathway gene loci examined, in particular, the replication factor C-1 (RFC1) gene variation may influence HNC risk.


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:
pica actually refers to the latin word for magpie , a bird thought to have odd feeding habits .
incidence of pica has also been linked to iron and zinc deficiency . whether the pica is an eating disorder or obsessive compulsive disorder is still controversial .
the patient was a 27 year old young indian lady living in the baruipur with no previous psychiatric or medical history .
patient complained of an unusual sensation in her abdomen for the last 3 months while her parents gave a history of habitual consumption of nails for the same duration .
the patient was a single child to her parents and she was living in the suburbs since her birth .
she had attended public schools and had completed her graduation on arts from a college in kolkata .
soon after her marriage , she expressed sexual aversion with history of dyspareunia . within a month of her marriage , she found it extremely difficult to live in her in - laws house and preferred to stay at her parental home , although her parents repeatedly insisted her to go back to her in - laws residence .
depressed and also admitted that for the last 3 months , she was having a sense of hopelessness and worthlessness over her future days .
vanished. she temporarily enjoyed the gritty and spiky sensation of nails along her throat , but at night she used to have a vague abdominal sensation which she described to be
funny. according to her mother , she did not want to go back to live with her husband . on close interviewing of the patient , initially her response to same- sex relationship was guarded but later it was found that she was actually having such a relationship with another lady of her age for the past 3 years .
she also accepted that she used to consume glass piece occasionally since last 3 years but never disclosed them to anyone .
she had once had an x - ray of her abdomen done 2 years back due to complaints of low back pain which was inconclusive ; perhaps glass beads which are radiolucent were missed . no further investigation was done .
the patient was decently dressed in a pastel shade salwar with a boyish cut hairstyle . on mental state examination
on interviewing the husband , it was known they had never had any sexual intercourse since marriage .
on routine examination , possibility of iron deficiency anemia , serum ferritin abnormality and zinc deficiencies were ruled out .
x ray of abdomen showed multiple radio opaque pointed objects in her gut ( ingested iron nails ) .
the patient had been nurtured in an overprotected environment by her parents in her early childhood days .
however immediately following her high school , she had to take many responsibilities of the family all of a sudden because of loss of job of her father .
she was more bonded to her mother and in the elderly , often avoided her father because he was alcoholic .
the cultural , psychodynamic , and physiological aspect of this case is a unique one . the patient 's initial experimentation with ingestion of glass beads , though in a very remote sense , may be culture based considering the fact that the practice of ingesting such beads and sharp metallic objects has been reported .
considering the fact that the patient was initially nurtured in an overprotected environment by her parents and suddenly being exposed to a comparatively hostile situation where she found a discouraging picture of the members of the opposite sex from that of her alcoholic father , the patient 's inclination toward same - sex relationship can be explained .
psychologically , the inclination of the patient toward same sex relationship and her unfamiliarity and uneasiness with the members of the opposite sex led to marital dissatisfaction . also ,
since the patient had to take many burdens of her family at an age which may be considered quite an early one considering the indian standards and her socioeconomic profile , this probably has caused her to resort to some , harsh robust means like  ingestion of nails which may have been an act to depict her
her intelligent quotient as measured by wechsler 's adult intelligence scale had been found to be 98 which fall in normal age .
as in most cases of pica , she initially did not come with a complaint of pica .
rather , she had reported to the hospital with complaints of unusual sensation in her abdomen .
the present case presented a unique conglomeration of cultural , psychodynamic , and physiological determinants which together contributed to the expression of pica in comparison with previous reports and reviews . however , an interesting fact in this case is the age of the patient which is quite unusual for pica to occur .
this perhaps necessitates further research in dealing with the epidemiology and other aspects of this quite rare but interesting disease entity .

Answer:
pica has been considered as the ingestion of inedible substances or atypical food combinations .
 pica has been reported widely in pediatric age group and often found to be co existing with obsessive compulsive or major depressive disorder .
 reports of pica in elderly age group are relatively uncommon and rarely does it have an adult onset . in this article we present a case of adult onset pica . a young lady with unusual sensation in her abdomen
 was found to consume iron nails over years and there was history of dyspareunia since her marriage three months back . on query
 it was known that the lady is having same sex relationship over years . there
 unique conglomeration of cultural , psychodynamic and physiological determinants which together is responsible for this unusual habit of this lady .
 moreover the onset of the disease at a late age and different psychodynamic issues make the case all the more interesting . whether the pica is an eating disorder or
 obsessive compulsive disorder is still controversial .
 pica has been mentioned in diagnostic and statistical manual iv tr .
 the present case report warrants the need to look into this entity more closely with regards to its occurrence and etiology .


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:
cystic fibrosis ( cf ) is the most common autosomal recessive disorder among caucasians with an incidence rate of 1 in 2,500 individuals . the epithelial cells of several organs , including respiratory tract , exocrine pancreas , intestine , vas deferens , hepatobiliary system and also exocrine sweat glands are involved in cf .
therefore several clinical features , including suppurative lung disease , pancreatic insufficiency , neonatal bowel obstruction ( meconium ileus ) , multifocal biliary cirrhosis , absent vas deferens to malabsorbtive condition and growth retardation could be seen in affected patients [ 2 , 3 ] .
high sweat electrolytes ( chloride and sodium ) concentration , which is seen in cf patients became basis for sweat chloride test since 1949 .
the measurement of sweat electrolyte concentrations was established as a standard procedure for diagnosis of cf and remained the gold standard test for the diagnosis of cf .
the diagnosis of cf could easily be made in the majority of cases based on typical clinical features and abnormal sweat chloride values . in such situations ,
genetic analysis of cystic fibrosis transmembrane conductance regulator ( cftr ) gene is not necessary .
however , it may be useful in confirming the diagnosis , which also enables carrier testing and prenatal diagnosis [ 6 , 7 ] .
the universally accepted reference intervals for sweat chloride concentrations regardless of age or sex are > 60 mmol / l , which is considered diagnostic of cf ; 4060 mmol / l is considered borderline , whilst < 40
in addition to sweat chloride concentrations , sweat sodium is also usually measured , as there is little difference between sweat sodium and chloride concentrations [ 810 ] in order to ensure accurate results from a quantitative sweat test using filter paper , a minimum sweat rate of 1g / m / min corresponding to 75 mg collected in 30 minutes is required ( for a 22 inch filter paper ) .
conventionally , it takes around 45 minutes to collect proper volume ( 50400 mg ) sweat for accurate test , which makes the classic sweat test as a time consuming procedure .
indeed many local laboratories in developing countries have not been approved to do the test for both techniques of sweat gathering and also electrolytes measuring . forming of salt crystallization of perspiration described by ferre calvete
et al   could be considered as a useful and alternative test for easy detecting cf patients in these regions .
therefore , we designed this study to compare the results obtained by these two methods . in this study , 60 children with clinical signs suggestive of cf , who were referred to the children 's medical center , pediatrics center of excellence in iran , were investigated .
the study protocol was approved by the research ethics board of the childrens medical center , tehran university of medical sciences .
classic sweat tests ( gibson and cooke sweat test ) and crystallization test were performed for each subject for at least two times in the referral laboratory of the hospital .
localized sweating was produced by iontophoresis of pilocarpine nitrate ( gibson and cook method ) using wescor gel discs [ 5 , 12 ] a copper electrode was then attached and a weak electrical current of about 3 milli - amperes ( ma ) was generated using a 9-volt battery for 5 minutes to stimulate sweating . immediately following stimulation ,
a preweighed filter paper was placed directly over the site of the positive electrode . at the end of the collection
about one hour later , the filter paper was removed and the weight was determined .
the test was repeated for two or three times in all subjects to confirm the results .
meanwhile one drop of each sample was put on lamella and heated by the light of microscope for 5 minutes .
sixty children ( 29 females and 31 males ) with age range of 9 months to 2 years had taken part in this study .
meq / l , while it was 49.81meq / l in the male group without any significant difference between genders ( p>0.05 ) .
cf was diagnosed for the remaining 29 patients who showed positive values of sweat classic test .
1 ) , which provided the test with 100% sensitivity ( ci : 93.1100 ) . only one of 31 subjects without cf ( 17 males and 14 females ; aged 9 months to 2 years ) had positive crystallization test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) .
crystal formation in sweat sample of cystic fibrosis patients cystic fibrosis ( cf ) is one of the most frequent ( 1 in 2500 ) autosomal recessive diseases characterized by substantial clinical heterogeneity recent studies have begun to identify chromosomal locations that identify specific genes contributing to this variation . over the past several decades , there has been substantial progress toward diagnostic tools of cf .
determination of chloride concentration in sweat is the current diagnostic gold standard for cf .

the conventional sweat test with elevated sweat sodium and chloride concentration after iontophoresis of pilocarpine is the standard laboratory test for cf .
an accurate sweat test relies on coordination of several factors . technical error of instrument calibration and result reporting
the tests should be performed by expert personnel to ensure sufficient sweat volumes and proper use of equipment .
the centers doing such tests should follow standard guidelines to reduce complexity in interpreting a variety of result ranges [ 14 , 15 ] advanced equipments and experienced personnel which are necessary for accurate classic sweat test made this test unavailable for many centers , especially in developing countries .
although sweat studies became standard diagnostic strategy for diagnosis of cf , it has some limitations whilst it may be unreliable due to not enough collected sweat or borderline values .
indeed genetic studies to detect cftr mutation(s ) take time and may even find no useful information . therefore selecting the best cost - benefit method with high sensitivity and specificity
is needed for diagnosis of cf . for this reasons nanoduct as a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes is also introduced as a reliable diagnostic tool .
nanoduct has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion , diagnosis or suspicion of cf .
sands and his colleagues indicated that simultaneous bilateral sweat testing with two different methods ( concentration and conductivity or nonoduct ) provides an extra quality control system , allowing more time efficient organization of the diagnostic and training procedures .

forming of salt crystallization of perspiration seems as an attractive and alternative test for easy detecting cf patients . in this study , we have shown that looking for salt crystals in just one drop of sweat could diagnose cf , since crystal formation of sweat under light microscope was detected in a significant number of cf patients .
comparing these two methods of sweat test showed good positive predictive value of 96.7% and the negative predictive value of 100% with specificity and sensitivity of 96.7% and 100% , respectively .
therefore , the test could be a very useful alternative test , whenever the classic test is not accessible .
since the classic sweat test measuring chloride levels with the use of acceptable methods ( gibson - cooke or wescor macroduct ) should be performed in centers that conduct sweat tests frequently with properly documented controls , we recommend sweat crystallization test as an alternative test for cf diagnosis at least in areas where neither classic sweat test nor genotyping are accessible .
limitations : there were some limiting factors to consider in interpreting the study 's result .
first , this study was conducted on a relatively small sample size . ideally , a larger and more popular sample size would perhaps delineate more suitable differences between the two methods of cf diagnosis in children with cystic fibrosis .
second , this study compared two kinds of test in children whose first presentation was compatible with cystic fibrosis , although this would not be statistically a problem .
as further study , comparing two methods of the mentioned tests between cf patients and normal children could be more helpful .
this study demonstrates the validity of sweat crystal formation test to support a diagnosis of cf in children whenever conventional sweat test is unavailable .
in this study , 60 children with clinical signs suggestive of cf , who were referred to the children 's medical center , pediatrics center of excellence in iran , were investigated .
the study protocol was approved by the research ethics board of the childrens medical center , tehran university of medical sciences .
classic sweat tests ( gibson and cooke sweat test ) and crystallization test were performed for each subject for at least two times in the referral laboratory of the hospital .
localized sweating was produced by iontophoresis of pilocarpine nitrate ( gibson and cook method ) using wescor gel discs [ 5 , 12 ] a copper electrode was then attached and a weak electrical current of about 3 milli - amperes ( ma ) was generated using a 9-volt battery for 5 minutes to stimulate sweating . immediately following stimulation ,
a preweighed filter paper was placed directly over the site of the positive electrode . at the end of the collection about one hour later , the filter paper was removed and the weight was determined .
the test was repeated for two or three times in all subjects to confirm the results .
meanwhile one drop of each sample was put on lamella and heated by the light of microscope for 5 minutes .
sixty children ( 29 females and 31 males ) with age range of 9 months to 2 years had taken part in this study .
meq / l , while it was 49.81meq / l in the male group without any significant difference between genders ( p>0.05 ) .
cf was diagnosed for the remaining 29 patients who showed positive values of sweat classic test .
1 ) , which provided the test with 100% sensitivity ( ci : 93.1100 ) . only one of 31 subjects without cf ( 17 males and 14 females ; aged 9 months to 2 years ) had positive crystallization test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) .
cystic fibrosis ( cf ) is one of the most frequent ( 1 in 2500 ) autosomal recessive diseases characterized by substantial clinical heterogeneity recent studies have begun to identify chromosomal locations that identify specific genes contributing to this variation . over the past several decades , there has been substantial progress toward diagnostic tools of cf .
determination of chloride concentration in sweat is the current diagnostic gold standard for cf .

the conventional sweat test with elevated sweat sodium and chloride concentration after iontophoresis of pilocarpine is the standard laboratory test for cf .
technical error of instrument calibration and result reporting are major factors that affect the results .
the tests should be performed by expert personnel to ensure sufficient sweat volumes and proper use of equipment .
the centers doing such tests should follow standard guidelines to reduce complexity in interpreting a variety of result ranges [ 14 , 15 ] advanced equipments and experienced personnel which are necessary for accurate classic sweat test made this test unavailable for many centers , especially in developing countries .
although sweat studies became standard diagnostic strategy for diagnosis of cf , it has some limitations whilst it may be unreliable due to not enough collected sweat or borderline values .
indeed genetic studies to detect cftr mutation(s ) take time and may even find no useful information . therefore selecting the best cost - benefit method with high sensitivity and specificity
is needed for diagnosis of cf . for this reasons nanoduct as a new analyzing system measuring conductivity which requires only 3 microliters of sweat and gives results within 30 minutes is also introduced as a reliable diagnostic tool .
nanoduct has a failure rate comparable to other sweat tests and can be used as a simple bedside test for fast and reliable exclusion , diagnosis or suspicion of cf .
sands and his colleagues indicated that simultaneous bilateral sweat testing with two different methods ( concentration and conductivity or nonoduct ) provides an extra quality control system , allowing more time efficient organization of the diagnostic and training procedures .

forming of salt crystallization of perspiration seems as an attractive and alternative test for easy detecting cf patients . in this study , we have shown that looking for salt crystals in just one drop of sweat could diagnose cf , since crystal formation of sweat under light microscope was detected in a significant number of cf patients .
comparing these two methods of sweat test showed good positive predictive value of 96.7% and the negative predictive value of 100% with specificity and sensitivity of 96.7% and 100% , respectively .
therefore , the test could be a very useful alternative test , whenever the classic test is not accessible .
since the classic sweat test measuring chloride levels with the use of acceptable methods ( gibson - cooke or wescor macroduct ) should be performed in centers that conduct sweat tests frequently with properly documented controls , we recommend sweat crystallization test as an alternative test for cf diagnosis at least in areas where neither classic sweat test nor genotyping are accessible .
limitations : there were some limiting factors to consider in interpreting the study 's result .
ideally , a larger and more popular sample size would perhaps delineate more suitable differences between the two methods of cf diagnosis in children with cystic fibrosis .
second , this study compared two kinds of test in children whose first presentation was compatible with cystic fibrosis , although this would not be statistically a problem .
as further study , comparing two methods of the mentioned tests between cf patients and normal children could be more helpful .
this study demonstrates the validity of sweat crystal formation test to support a diagnosis of cf in children whenever conventional sweat test is unavailable .

Answer:
objectivesweat chloride measurement is considered a standard diagnostic tool for cystic fibrosis ( cf ) .
 this study was performed to compare sweat chloride values obtained by quantitative pilocarpine iontophoresis ( classic test ) with sweat crystallization detected by direct observation of a drop of perspiration under light microscopy in patients with and without cf.methodsthe tests using both techniques were performed simultaneously in patients with and without cf .
 cutoff values of 60 mmol / l of chloride concentration for the classic sweat test was considered for diagnosis of cf . in crystallization method ,
 observation of typical dendritic forms of salt crystals under light microscopy was interpreted positive.findingssixty patients suspected to cf ( 31 males and 29 females ) with age range of 9 months to 2 years underwent the sweat test using both techniques .
 median sweat chloride values was 26.13 + 10.85 in group with negative and 72.76 + 12.78
 mmol / l in group with positive sweat test , respectively .
 all the patients who had positive sweat test in classic method showed typical dendritic forms of salt crystal in sweat crystallization test , which provided the test with 100% sensitivity ( 95%ci : 93.1100 ) .
 only one of the 31 subjects with negative results for classic sweat test had positive result for crystallization sweat test , which provided the test with 96.7% specificity ( 95%ci : 92.9100 ) .
 time spent to perform the crystallization test was significantly shorter than the classic method whereas its cost was also lower than the second method.conclusionthere was a good correspondence between two studied methods of sweat test .
 these results suggested the sweat crystallization test as an alternative test for detecting cf disease with high sensitivity and specificity .


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:
waldenstrom 's macroglobulinemia ( wm ) is the result of a clonal proliferation of lymphocytes that produce monoclonal immunoglobulin m ( igm ) .
it is now considered to correspond to lymphoplasmacytoid lymphoma as defined by the world health organization classification system ( 1 , 2 ) .
many central nervous system ( cns ) complications have been described in wm patients ; the majority have been associated with blood hyperviscosity caused by igm .
the hyperviscosity syndrome is characterized by headache , tinnitus , vertigo , blurred vision , and chronic bleeding from the nose and gums ( 3 ) .
however , cns infiltration by plasmacytoid lymphocytes ( bing - neel syndrome ) has only rarely been reported ( 4 ) .
a 51-yr - old woman was diagnosed with wm three years prior to this presentation .
she received six courses of chlorambucil ( 0.3 mg / kg per day on day one to four orally ) and prednisone ( 45 mg / m per day on day one to four ) .
next , she received fludarabine chemotherapy ( 25 mg / m per day on day one to five intravenously ) with a limited response .
high - dose cyclophosphamide and granulocyte colony - stimulating factor were administered to induce peripheral blood progenitor cell ( pbpcs ) mobilization for autologous stem - cell transplantation ; however , the number of pbpcs collected was not sufficient .
we then decided on a conservative treatment approach , because the patient did not have specific symptoms and the serum igm level was stable ( 3,000 - 3,500 mg / dl ) .
the laboratory values on admission were as follows : white cell count 8,050/l with normal differential counts , hemoglobin 9.6 g / dl , platelets 296,000/l , erythrocyte sedimentation rate 144 mm / hr , total protein 9.44 g / dl , albumin 2.85 g / dl , igg 3144.4 mg / dl , iga 25.4 mg / dl , igm
a brain computed tomography scan revealed multifocal extra - axial tumorous lesions along the dura matter .
a brain magetic resonance imaging showed an extra - axial soft tissue tumor along the left cavernous sinus and tentorium , right frontal convexity and tentorium and falx ; the brain parenchyma appeared to be unremarkable ( fig .
cerebrospinal fluid analysis showed the following : white cell count 43/l with neutrophils 1% , lymphocytes 52% and monocytes 47% , total protein 1.81 g / dl , glucose 104 mg / dl , igm 64.5 mg / dl and a few plasmacytoid lymphocytes on cytology .
stereotactic biopsy of dural tissue at the falx showed a diffuse infiltration with atypical cells , which were identified immunophenotypically as plasmacytoid lymphocyte with expression of lca ( + ) , cd3 ( - ) , cd20 ( + ) , and vs38a ( + ) ( fig .
2 ) . the patient was confirmed to have cns infiltration by atypical plasmacytoid lymphocyte infiltration ( bing - neel syndrome ) .
the paitent received a total dose of 1,980 cgy with irradiation therapy of the whole brain that was administered in 11 fractions , and then her headache subsided , but the igm level was elevated persistently to 3,379.8 mg / dl . following radiation therapy ,
fludarabine chemotherapy was performed ( 25 mg / m per day on 1 to 5 intravenously , two courses ) .
a follow - up brain mri after six months revealed a marked decrease in the size of the mass in the tentorium and falx ( fig .
the patient had no evidence of cns recurrence during the follow - up period of one year
. however , the igm level has been increasing slowly , so further chemotherapy , including rituximab may be considered .
in 1936 bing and neel reported the association of hyperglobulinemia , cns symptoms ( paresthesias , headache , and paralysis ) , and brain infiltration composed of plasma cells and lymphocytes in two patients ( 5 ) . in 1944 , waldenstrom described the syndrome that bears their name ( bing - neel syndrome ) ( 6 ) .
the bing - neel syndrome , originally placed in a " toxic - infectious " category , appears to be the result of involvement of the cns by diffuse neoplasm infiltration .
although they are most often peripheral , they can involve the cns . in wm , the cns may be involved by a variety of mechanisms , including hyperviscosity and direct infiltration by neoplastic cells ( 7 , 8) .
patients with bing - neel syndrome have sometimes presented with a mass containing neoplastic cells , but the masses have been intraparenchymal rather than meningeal ( 8 , 9 ) .
this syndrome can be subdivided into diffuse and tumoral forms . in the diffuse infiltrative form such as this case
, malignant cells are localized mainly in leptomeningeal spaces , periventricular white - matter , pons , and medulla ( 7 , 10 - 12 ) .
radiological findings in this syndrome have been reported , but a typical pattern has not emerged ( 13 - 15 ) . an imaging technique would be the preferable diagnostic test , although histological confirmation is necessary to establish the definitive diagnosis .
intraventricular chemotherapy for bing - neel syndrome was reported to be effective in 1984 ( 15 ) .
however , a review of the literature reveals that the outcome for most patients who underwent chemotherapy was poor , and the patients died within several months ( 10 , 13 , 14 ) .
therefore , patients with bing - neel syndrome may benefit from cranial radiation therapy prior to chemotherapy ( 9 , 12 , 16 ) .
recently , a great deal of interest has been noted by treatments with purine nucleoside analogs ( fludarabine , cladribine , and pentostatin ) because of their remarkable activity in lymphoproliferative disorders .
it has been reported that a patient with bing - neel syndrome ( in its diffuse form ) was successfully treated with cladribine administration ( 17 ) , or radiation therapy and combination of cladribine , cyclophosphamide , and prednisone ( 18 ) . in the present case
further treatment was not possible because of persistant bone marrow suppression . a follow - up brain mri after six months revealed a marked decrease in the size of the mass in the tentorium and falx ; the patient had no evidence of cns recurrence during the follow - up period of one year , but the igm level has been increasing slowly . we think that the major effect of deceased mass size was due to the radiation therapy in the present case .
several retrospective and prospective studies have indicated that rituximab may induce an objective response in approximately 30 - 40% of previous treated patients with wm ( 19 ) .
however , the effect of rituximab treatment on the cerebrospinal fluid b - cell compartment is limited in comparison with the effect on the b cells in the periphery ( 20 ) , and it has not been tried in bing - neel syndrome as yet . therefore , the effect of rituximab on cns involovement of wm need to be validated by of future studies .

Answer:
waldenstrom 's macroglobulinemia is an uncommon low - grade b - cell lymphoproliferative disorder in which monoclonal immunoglobulin m is produced .
 neurological symptoms due to hyperviscosity are frequent manifestations of waldenstrom 's macroglobulinemia . however , central nervous system infiltration by plasmacytoid lymphocytes ( bing - neel syndrome ) has only rarely been reported .
 we report a case of a 51-yr - old woman suffering from waldenstrom 's macroglobulinemia who complained of persistant headache .
 brain magnetic resonance imaging revealed an extra - axial soft tissue mass along the left cavernous sinus , left tentorium , right tentorium , and falx cerebri . a stereotactic biopsy of dural tissue from the falx was performed and showed plasmacytoid lymphocyte infiltration .
 the patient became symptom- free with irradiation of the whole brain followed by chemotherapy with fludarabine .


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:
urinary tract infection ( uti ) is the most common infection contracted by renal allograft recipients . in patients of autosomal dominant polycystic kidney disease ( adpkd )
, cyst infection presents a complex diagnostic and therapeutic challenge , especially in the post transplant period .
consequently , early and reliable detection of infected renal cyst is crucial for optimal patient management , especially when initial antibiotic therapy has failed .
it has been infrequently reported in the post transplant scenario or in the adpkd patients .
we report a case of post transplant xpn in the native adpkd kidney presenting as relapsing uti .
18-fluorodeoxyglucose ( fdg)-positron emission computerized tomography ( pet / ct ) scan allowed the exact localization of the infection in the renal parenchyma and guided the therapeutic procedure with subsequent resolution of uti .
a 53-year - old male of adpkd - ckd on maintenance hemodialysis since one and half years received a deceased donor renal transplant at our institute .
his postoperative recovery was uneventful and he was discharged on tenth post transplant day with a serum creatinine of 1.2 mg / dl .
he presented two weeks later with complains of fever , malaise and dysuria . on clinical examination , he was hemo - dynamically stable but febrile .
laboratory parameters included hemoglobin 10.2 gm / dl , leukocytes 8,600/cmm , platelets 2.9 lacs / cmm , glucose 186 mg / dl , urea 18 mg / dl , serum creatinine 1.7 mg / dl , sodium 138 meq / l , potassium 4.3 meq / l .
urine analysis showed , albumin 1 + , 40 - 50 leukocytes /high power field ( hpf ) , red cells 4 - 5/hpf , no casts , bacteria , acid fast bacilli or fungus were found .
chest x - ray was normal , abdominal ultrasonography showed multiple hepatic and renal cysts in native kidneys , but was not suggestive of any infection , graft kidney was unremarkable .
he was treated with antibiotics and responded well to the same and later discharged . over the next three months patient presented twice with symptoms of uti and the urine cultures on both occasions grew escherichia coli .
he was evaluated with ultrasonography and unenhanced computerized tomography ( ct ) , which revealed a normal transplant kidney and multiple cysts without evidence of any infection , hemorrhage or calculi in native kidneys .
subsequently , patient underwent cystoureteroscopy with bilateral selective urine sampling from native kidneys , however culture revealed no growth . in an attempt to localize the source of infection
it showed hyper - metabolic lesion arising in postero - inferior part of right native kidney [ figure 1 ] .
pet / ct guided aspiration reveled purulent fluid , culture of the same yielded heavy growth of e. coli . on the basis of these findings , patient was subjected to right native kidney nephrectomy .
the cut section of the gross specimen showed xanthomatous area [ figure 2 ] and the histopathology was suggestive of xpn [ figure 3 ] .
patient made a good recovery with s. creatinine returning to 1.3 mg / dl and urine culture being sterile on subsequent follow - up of three months .
pet / ct scan showing strong fdg uptake into postero inferior part of right native kidney ( arrow ) gross section of right kidney showing xanthogranulomatous area ( arrow ) light micrograph showing an interstitial infiltrate composed of neutrophils , mononuclear cells , and , most characteristically , lipid - laden macrophages ( arrow ) .
febrile illness owing to complicated uti 's secondary to renal or hepatic cyst infection is a common cause of graft dysfunction .
if not localized early and redressed they can be a source of significant morbidity especially in an immuno - compromised host .
it is characterized by replacement of renal parenchyma with diffuse or segmental cellular infiltrate of lipid laden macrophages called foam cells .
here , we report a case of rare occurrence of xpn in native polycystic kidney of a renal allograft recipient . in the literature ,
xpn in adpkd either in transplant scenario or otherwise has been infrequently reported.[46 ] in our case , conventional ct scan was non - contributory , however fdg pet / ct scan was helpful in localizing the site of infection .
as the patient was not responding to conservative management it was decided to proceed with nephrectomy of infected kidney .
xpn was subsequently established on evaluation of gross specimen [ figure 2 ] and histopathology [ figure 3 ] .
fdg pet / ct scan in the recent times has emerged as a valuable tool for the transplant physician in localizing of infections especially in adpkd patients .
pet / ct can overcome interpretive challenges in identifying tissue infection , based on the high metabolic activity and increased uptake of the glucose - analogue fdg by inflammatory cells .
post transplant , uti especially in the adpkd patients is challenging to the transplant physician .
this case highlights the rare occurrence of xpn as a cause of post transplant uti , especially in the absence of obstruction or stone disease .
fdg pet / ct imaging is a valuable tool in both localization and subsequent planning of therapeutic interventions for complicated utis associated with adpkd transplant patients .

Answer:
urinary tract infection ( uti ) is the most common infection contracted by renal allograft recipients . in patients of autosomal dominant polycystic kidney disease ( adpkd )
 , cyst infection presents a complex diagnostic and therapeutic challenge especially in the post transplant period .
 accurate diagnosis forms the cornerstone in salvaging the graft from potentially catastrophic outcome .
 we describe a case of xanthogranulomatous pyelonephritis ( xpn ) in the native kidney in a patient of post transplant adpkd which presented as frequently relapsing uti with graft dysfunction where in accurate diagnosis was made possible with the aid of 18-fluorodeoxyglucose ( fdg ) - positron emission computerized tomography ( pet / ct ) .


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:
frontalis sling surgery is the treatment option for myopathic blepharoptosis with poor levator muscle action .
nontuberculous mycobacterial infections in the periocular region are rare and are usually caused by organisms belonging to runyon group iv including mycobacterium chelonae and mycobacterium fortuitum .
chang et al . reported six cases of nontuberculous mycobacterial infection and found an association with nasolacrimal duct obstruction , implantation of foreign body , history of recent surgery , and immunosuppression .
mauriello found implantation of a foreign body in 5 out 13 patients of nontuberculous mycobacterial infections of the periocular region .
treatment of nontuberculous mycobacterial infections can be difficult because of their multi - drug resistance .
treatment usually involves surgical debridement with removal of infected foreign body and a prolonged course of antibiotics like amikacin , clarithromycin , ciprofloxacin , and doxycycline .
we report a rare case of nontuberculous mycobacterial infection of the silicone rod after frontalis sling surgery .
a 65-year - old apparently healthy male presented with complaints of pain and swelling of both eyelids of 2  months duration .
he had undergone cataract and frontalis sling surgery for myopathic blepharoptosis in both eyes 2  years prior to presentation .
the best corrected visual acuity for distance was 20/400 in right eye and 20/25 in the left eye .
examination of face showed multiple , erythematous nodules involving both upper eyelids and the brow .
all nodules were localized to the scars from the previous ptosis surgery with a few showing signs of suppuration ( fig .
the posterior segment showed hypertensive retinopathy in both eyes and a scar at the macula in the right eye .
systemic workup was unremarkable and included a complete blood picture , chest x - ray and serological tests for hiv .
the patient was clinically diagnosed to have chronic progressive external ophthalmoplegia status post bilateral frontalis sling and cataract surgery with multiple abscesses in forehead and upper eyelids .
the patient underwent an incision and drainage of the abscesses in the brow and the purulent material was sent for microbiological examination .
the smear showed the presence of acid fast bacilli on 20  % acid fast staining ( fig .
1b ) and culture was significant for staphylococcus sp . and m. fortuitum ( fig .
the patient received intravenous amikacin ( 1  g / day , single dose ) and ciprofloxacin ointment locally .
poor response to treatment necessitated exploration with explantation of the silicone rod sling in the right eye 10  days later .
a repeat microbiological evaluation showed acid fast bacilli and significant growth of m. fortuitum on culture .
as the isolate showed a similar antibiotic sensitivity pattern the patient was continued on intravenous amikacin ( 1  g / day ) .
however , 11  days later , the patient suffered from another episode of pain and swelling in the left eye .
a repeat exploration of the brow with drainage and silicone rod explantation was performed in the left eye .
the patient showed a slow but definite improvement and received intravenous amikacin for 6  weeks .
five months after commencement of therapy the patient was asymptomatic and the left upper eyelid position was maintained ( fig .
1a an apparently healthy 62-year - old man presented with painful , erythymatous nodules of bilateral brow and upper lids two years after frontalis sling surgery for severe myopathic ptosis .
b microscopic picture of the purulent material showing long , slender acid fast bacilli along with polymorphonuclear cells ( ziehl neelsen stain , total magnification 1,000 ) .
c sheep blood chocolate agar inoculated with purulent material along with silicone tube ( left eye brow after 11  days of treatment ) shows confluent growth of cream colored , opaque , medium size colonies of staphylococcus aureus and tiny , semi - opaque colonies of mycobacterium fortuitum ( incubation : 4  days , 5  % co2 , 37  c ) .
d five months after sensitivity - based antibiotic treatment and explantation of bilateral silicone rods , the patient showed resolution of symptoms .
the left upper eyelid maintained an elevated position after silicone rod explantation a an apparently healthy 62-year - old man presented with painful , erythymatous nodules of bilateral brow and upper lids two years after frontalis sling surgery for severe myopathic ptosis .
b microscopic picture of the purulent material showing long , slender acid fast bacilli along with polymorphonuclear cells ( ziehl neelsen stain , total magnification 1,000 ) .
c sheep blood chocolate agar inoculated with purulent material along with silicone tube ( left eye brow after 11  days of treatment ) shows confluent growth of cream colored , opaque , medium size colonies of staphylococcus aureus and tiny , semi - opaque colonies of mycobacterium fortuitum ( incubation : 4  days , 5  % co2 , 37  c ) .
d five months after sensitivity - based antibiotic treatment and explantation of bilateral silicone rods , the patient showed resolution of symptoms .
several authors have reported about nontuberculous mycobacterial infections after periocular surgery [ 3 , 4 ] .
the median time interval between prior surgery and onset of infection in these reports was 6  weeks ( range 0.511  months ) [ 3 , 4 ] . in our patient , multiple erythematous nodules with suppuration along the tract of the silicone rod more than 2  years after surgery led to the suspicion and eventual diagnosis of nontuberculous mycobacteria . some aspects in our patient need to be highlighted .
first is that a bilateral infection by nontuberculous mycobacteria involving the silicone rod after frontalis sling surgery has not been reported earlier .
the lodgement of nontuberculous mycobacteria in the brow region in our case may be related to the persistent irritation from the silicone rod and its predeliction for fat [ 4 , 5 ] .
sequestration of nontuberculous mycobacteria with fat allows its growth without detection by normal immunosurveillance [ 4 , 5 ] . in our patient ,
sequestration of nontuberculous mycobacteria in the brow fat may have been responsible for delayed and bilateral infection involving the silicone slings .
further , fitzgerald et al . found nontuberculous mycobacteria in 82  % of fat globules in their series of 71 cases .
complete resolution in our case occurred only after silicone slings were removed from both eyes .
finally , removal of the silicone sling did not result in a recurrence of blepharoptosis .
this phenomenon is postulated to be due to scarring and fibrosis along the tract of the silicone rod .
nontuberculous mycobacterial may be responsible for bilateral delayed infection after frontalis surgery with silicone slings in an immunocompetent adult .
surgical removal of infected slings and prolonged course of antibiotics are required for complete resolution .
the authors do not have any financial interest or any conflicting relationship in any of the issues or products referred to in the manuscript .
this article is distributed under the terms of the creative commons attribution license which permits any use , distribution and reproduction in any medium , provided the original author(s ) and source are credited .

Answer:
purposethe purpose of this study is to report a case of nontuberculous mycobacterial infection after frontalis sling surgery.methoda 65-year - old man presented with bilateral painful , erythematous lesions in the brow and upper eyelids .
 he had a history of frontalis sling surgery for myopathic ptosis 2  years back and all lesions were found localized to the tract of the silicone rod used in the previous frontalis sling surgery.resultincision and drainage of the lesions with microbiological analysis revealed significant growth of coagulase negative staphylococcus and mycobacterium fortuitum .
 sensitivity - based antibiotic treatment with intravenous amikacin was started , but poor response necessitated eventual explantation of both silicone rods for relief of symptoms .
 culture of the explanted rods revealed similar results of m. fortuitum infection .
 five months after the acute presentation , the patient is asymptomatic.conclusionnontuberculous mycobacterial infection may be a delayed onset complication in frontalis sling surgery using silicone rods .


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:
genome - wide association ( gwa ) analysis has provided the first effective strategy to allow a systematic dissection of the genetic basis of common , complex , multifactorial traits .
although for many of these we remain some distance from a complete enumeration of causal mechanisms , there have already been substantial advances in understanding of disease - the role of autophagy in inflammatory bowel disease   and cell adhesion in autism , for instance . however , for most common traits the proportion of the overall phenotypic variance explained remains small , limiting the extent to which prediction of individual disease risk is possible .
there is growing speculation about the mechanisms that might account for the substantial proportion of trait heritability that remains to be characterized .
this speculation has repercussions well beyond recondite theoretical discussion about the genetic architecture of complex traits .
with advances in technology ( particularly next - generation sequencing ) and growing enthusiasm for funding large - scale gene discovery efforts , hypotheses about the nature of this so - called ' genetic dark matter '   have a direct bearing on research strategies .
recently , this debate has seemed increasingly polarized between those who feel a continued search for common susceptibility variants is of limited value , because all that remains to be found are variants of vanishingly small effect , and those who feel that , pending reductions in costs that will allow high - quality , whole - genome sequence data to be generated in adequately powered sample sizes , there is virtue in persisting with an approach of proven worth .
there is good reason to assume that this ' dark matter ' is neither an illusion created by inflated estimates of heritability nor the consequence of marked non - additivity of effects .
if so , then the sum total of genetic variance should largely be explicable in terms of the main effects of all the risk alleles of various types ( single nucleotide polymorphisms , indels , copy number variants ( cnvs ) and inversions ) , allele frequencies ( rare , low - frequency and common ) and effect sizes .
so far , the only parts of this ' space ' explored systematically are those occupied by rare , penetrant alleles ( principally through linkage analysis of monogenic phenotypes ) and common , mostly low - effect alleles ( accessible through gwa analysis ) .
as we seek to make sensible decisions about the direction of future discovery efforts - in terms of the characteristics of the variants we are seeking and the technologies we should use to find them - we need to understand what the exploration of the ' known ' genetic landscape can tell us about the parts that remain largely uncharted .
one long - standing view is that complex trait susceptibility is predominantly a matter of common variants .
common variants collectively account for most individual variation in dna sequence , and the same might be expected to be the case for phenotypic variation .
if true , the results of gwa studies so far indicate that most of the as - yet - undiscovered variants must ( in europeans at least ) have very small effects , because the high coverage and large sample sizes used will have left few , if any , large common - variant effects undiscovered .
evidence ( for example , from large - scale meta - analyses ) is , for many traits , consistent with the notion of a long ' polygenic tail ' of small effects , but it remains unclear how much of overall heritability can be explained under this model .
the idea that complex - trait susceptibility involves a very large number of variants of modest effect has led some to suggest that the value of all such discoveries is diminished , on the basis that one learns little about the biology of disease if too many genes are implicated . however , for many phenotypes , the overall salience of the loci of greatest effect emerging from gwa studies ( the pathways implicated and the relationships to monogenic forms of the same traits ) argues forcefully against such a nihilistic interpretation .
the contrasting viewpoint holds that common - trait susceptibility derives mostly from the action of rare or low - frequency variants .
although such variants account for less individual sequence variation than common variants , there may be a disproportionate effect on disease susceptibility .
the more recent origin of low - frequency variants may allow alleles with more dramatic phenotypic effects to be represented in the population . also , large - effect alleles may cause phenotypic disturbances that are not as easily buffered by compensatory changes during development as are well tolerated , small - effect , common - variant alleles .
recent evidence that large , rare cnvs are associated with behavioral and psychiatric disease phenotypes   supports this view .
some argue that such a rare variant architecture is precisely what one would expect for diseases causing low reproductive fitness , though this rationalization fails to explain the high yield of common - variant signals reported for other diseases , such as type 1 diabetes , that were , until recently , fatal during early life .
it has even been suggested that many of the common - variant associations discovered by recent gwa studies may turn out to be due to the concerted action of multiple low - frequency and rare causal variants .
the nod2 ( card15 ) signal for crohn 's disease indicates that this is certainly possible . for many diseases ,
however , evidence that common - variant associations are consistent across multiple ethnic groups   represents a strong counter to such a model : one would expect the linkage disequilibrium patterns around recent rare and low - frequency causal variants to result in far more inter - ethnic heterogeneity than is actually observed .
although both extreme positions have merit , the likelihood is that , for most diseases , the architecture of predisposition features causal variants that have a wide range of allele frequencies and effect sizes . for most complex traits
, the absence of compelling signals from linkage studies conducted in families segregating multifactorial diseases imposes an upper bound to feasible effect sizes ; even so , it is easy to show that a limited number of low - frequency susceptibility alleles of medium effect could go a long way to explaining missing heritability .
for example , the effect of a low - frequency variant with a population minor allele frequency of 1% and a per - allele odds ratio of 3 , when measured in terms of sibling relative risk ( a commonly used measure of familial aggregation ) , exceeds that of the largest common - variant effect known for type 2 diabetes ( around tcf7l2 ) .
twenty such variants across the genome would account for most of the unexplained heritability for this condition .
such a constellation of variants could provide a respectable tool for individual disease prediction , and the variants discovered would ( because of their relatively large effect size ) be valuable resources for detailed molecular and physiological study
. the extent to which variants with these characteristics are segregating in the population remains unknown , but this is an area in which the combination of next - generation sequencing technologies and large - scale association analysis provides a powerful stimulus to discovery .
early results of this approach ( such as the identification of low - frequency variants within the ifih1 gene that have a marked effect on type 1 diabetes susceptibility ) are encouraging .
ultimately , we can expect large - scale , high - depth , genome - wide sequencing to enable the systematic exploration of the entire allele - frequency , effect - size space and provide empirical resolution of many of these issues .
however , there remain serious financial , logistical and analytical barriers to the implementation of this technology , and the number of such experiments that could be supported by the major funders is , for the time being , limited .
all this means that , for the next few years , the power of next - generation sequencing will need to be used carefully if a profusion of underpowered discovery efforts is to be avoided .
efforts targeted to specific genomic regions ( around particular candidate genes or pathways or exons across the genome , for example ) are attractive because high coverage of the selected areas in large sample sizes can be generated at reasonable cost .
whole - genome sequencing will , for now , be restricted to low - pass coverage across respectable sample sizes , or high - depth coverage in smaller , highly selected , phenotypically extreme sample sets .
the genomic distribution of disease - effect loci will have a major impact on the success of these alternative approaches ( figure 1 ) .
if the low - frequency and rare variants influencing a given trait are disproportionately located in the same loci as the common variants that have been found to date , then targeted follow - up of regions revealed by gwa studies will be a powerful approach , and extending the range and scope of gwa analysis ( to other ethnic groups , for example ) should be a particularly efficient strategy . if , on the other hand , the ' dark matter ' variants have little positional ( or biological ) overlap with those already known , then genome - wide resequencing is likely to be the only practical way to find them .
the evidence so far ( overlap between monogenic and multifactorial loci ; growing numbers of loci with multiple independent association signals ; extensive pleiotropy , and so on ) provides some support for the former view .
effort in tracking down common susceptibility variants , as well as being valuable in its own right , should therefore guide researchers towards other types of causal variants .
two possible versions of the state of nature are presented ( see text ) . in one ( ' even ' ) , causal variants differing in terms of allele frequency ( color scale ) and effect size ( height of bar ) are distributed randomly across the genome : the location of common - variant ( red / orange ) associations of modest effect provides no guide to the location of lower - frequency variants ( yellow / green ) , some of which have quite large effects . in the other ( ' lumpy ' ) , causal variants congregate around certain genomic positions ( ' genes ' ) : gwa studies that reveal the location of the common - variant associations will also reveal the positions of lower - frequency variants , and the proportion of disease biology explained by the loci discovered through gwa studies will be far greater than the proportion of variance explained would suggest .
with only limited empirical data to guide future locus - discovery efforts , extrapolation from the modest proportion of genetic variance so far explained is fraught with danger .
the menu of possible research strategies is large , but each choice makes some implicit assumption about the characteristics of the variants being sought and the genomic architecture of the disease under consideration . given uncertainties over the true state of nature , it is difficult to say which approaches will be most productive .
this argues for open minds , a healthy disdain for orthodoxy , and careful exploration of the technological and methodological options . at the same time
, it is important that the next wave of large - scale discovery efforts is designed so as to test assumptions about trait architecture and technological performance so that lessons of generic value to the field can be learned .
i thank the many colleagues around the world who contributed to the discussions that informed this article .

Answer:
identification of common - variant associations for many common disorders has been highly effective , but the loci detected so far typically explain only a small proportion of the genetic predisposition to disease .
 extending explained genetic variance is one of the major near - term goals of human genetic research .
 next - generation sequencing technologies offer great promise , but optimal strategies for their deployment remain uncertain , not least because we lack a clear view of the characteristics of the variants being sought . here
 , i discuss what can and can not be inferred about complex trait disease architecture from the information currently available and review the implications for future research strategies .


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:
neonatal diabetes mellitus ( ndm ) is a rare monogenic form of diabetes starting within the first 6  months of life 13 .
the disease has an incidence of about 1:100,000260,000 live births and can be permanent ( pndm ) , requiring lifelong treatment , or may be transient ( tndm ) , in which case the diabetes may spontaneously remit ( or be so mild as not to require treatment ) , but will often relapse , usually during adolescence 35 .
a genetic diagnosis has been made in up to 90% of these patients 7 . in the majority of them
( around 70% ) , it was found that a genetic or epigenetic alteration in the tndm locus on chromosome 6q24 causing the overexpression of two imprinted genes 7 .
less frequently , activating mutations of the genes kcnj11 and abcc ( accounting for 10% and 13% of the cases , respectively ) may result in tndm 7 .
mutations in these genes lead to a gain - in - function of the pancreatic atp - sensitive potassium ( katp ) channel , which is critical in the regulation of insulin secretion by the beta cell 3,6,8,9 .
the beta cell katp channel is an octameric complex composed of four pore - forming subunits : channel - building inwardly rectifying potassium - channel subunits ( kir6.2 ) encoded by the kcnj11 gene , and four regulatory sulfonylurea - receptor subunits ( sur1 ) and encoded by the abcc8 gene 10,11 .
these subunits regulate the metabolic activity of the channel , which is shut down in response to an increase in intracellular atp , leading to insulin secretion .
gain - in - function mutations of either of these genes keep the channel in open conformation and impair insulin secretion 1012 .
most patients with kcnj11 mutations treated with insulin can be transferred to sulfonylurea ( su ) with a remarkable improvement in metabolic control and patient 's quality of life 13 .
sulfonylureas close katp channels , through an atp- independent route , improving insulin secretion and representing a suitable therapeutic alternative for patients with kcnj11 mutations 10 . for these reasons ,
identification of katp channel mutation can have a major impact on the treatment 's choice .
this is an example about how molecular diagnosis can influence the clinical management of the patients .
herein , we report on a case of ndm in a caucasian boy , who presented severe diabetic ketoacidosis ( dka ) at 17  days of life .
the genetic screening showed a heterozygous missense mutation ( c.679  g > a ) in the kcnj11 gene which leads to the replacement of lysine with glutamic acid at position 227 ( e227k ) of the atp sensitive potassium channel .
an 11-day - old caucasian boy was admitted to the neonatal care unit with complaints of poor weight progression , suppurative conjunctivitis , and mucoral candidiasis .
he was the second child of a 21-year - old woman ( gravida 2 , para 1 ) without history of diabetes , and was born through cesarean section at 38  weeks of pregnancy due to preeclampsia .
apgar score was 5/9/10 ; birth weight was 2890  g ( p15 ) , length 47  cm ( p15 ) and head circumference 34.5  cm ( p50 ) 14 . on physical examination ,
the infant exhibited axial hypotonia and weak suction reflex , demanding a nasogastric tube in order to be feed . at 17 days
the child became irritable , drowsy , dehydrated , tachypneic , tachycardic with poor peripheral perfusion ; rectal temperature was 37.8c .
he was started on intravenous vancomycin after isolation of a methicillin - resistant staphylococcus from the axillary suppurative adenitis .
blood tests revealed a glycemia of 1412  mg / dl with high levels of ketonemia ; serum sodium was 172
mmol / l ; potassium 3.9  mmol / l , and the ph was 7.0 .
after initial treatment with intravenous 0.9% saline serum , he was started on intravenous insulin perfusion ( 0.01  u / kg / h ) in a 0.45% saline serum supplemented with 15  meq / l of potassium chloride .
three days later , the insulin perfusion was stopped and the child was transferred to a subcutaneous protocol of intensive insulin therapy , consisting in a once daily administration of insulin glargine ( 1  u / day ) , and insulin lyspro every 6  h. further investigations revealed that there was no evidence of pancreatic exocrine failure .
transfontanelar and abdominal ultrasounds ; electroencephalography and brain magnetic resonance imaging showed no relevant findings . an interatrial communication
 ostium secundum  , associated with enlargement of right cavities was found in the echocardiogram .
c - peptide was 0.37  ng / ml ( 0.804.20 ) ; auto antibodies against islet cell ( ica ) , decarboxylase of glutamic acid ( gad ) , and insulin were all negative .
the infant was referred to a tertiary hospital due to instability of his metabolic control , alternating episodes of hypoglycemia with hyperglycemia .
two months later , insulin administration was stopped , given that glycemia was always within normal levels with minimal amounts of insulin . at this stage ,
the c - peptide was already normal . at the age of 9  months , his growth had declined from p10 to p<1 .
the e227k mutation found in our patient is a gain - function mutation that results in both impaired atp sensitivity and higher intrinsic
the e227k mutation has been reported in several other patients with tndm but also in a few with pndm reflecting the phenotypic variability of kcnj11 mutations ( table1 ) .
the reason why the same mutation causes a relapsing / remitting form of diabetes in some patients whereas in others it produces a permanent diabetes is unclear 15 .
it was not demonstrated a clear relationship between the clinical phenotype and the magnitude of the impairment of the atp - sensitive potassium ( katp ) channels .
tndm may result from a reduction in insulin requirements at the time of remission due to changes in beta cell turnover or to compensatory alterations ( at the level of the beta cell , pancreas , or whole body ) , overcoming the lower effectiveness of the atp sensitive potassium channel .
therefore , the genetic background of the patient as well as other still unrecognized environmental factors may play an important role in the phenotypic expression of the mutation . on the other hand
, the apparent clinical variability may result from confounding factors : patients diagnosed during puberty or early adulthood may have had a period of hyperglycemia that was missed during the neonatal period .
clinical data of patients with heterozygous e227k mutation wks , weeks ; mth , months ; yrs , years ; dka , diabetic ketoacidosis ; mody , maturity - onset diabetes of the young . the e227k may be inherited from affected parents , or occurs as de novo mutation . in our study , the mutation is present in the affected child but also in his asymptomatic mother , suggesting that there was not a complete co - segregation of the mutation with diabetes .
this situation has also been described previously ( table1 ) . in the majority of tndm and
pndm cases caused by kcnj11 mutations 3,13 , including e227k mutations 11 , metabolic control was achieved by replacing insulin therapy with sulfonylureas , which are well - known katp channel inhibitors ( table1 ) .
this finding supports the idea that if our patient has a relapse of diabetes , he may achieve optimal glycemic control with oral sulfonylurea treatment , strengthening the importance of the molecular diagnosis even if neonatal diabetes remits .
the expression of kcnj11 in the central nervous system and skeletal muscle explain the neurological features associated with syndromic forms of pndm , such as developmental delay , muscle weakness , and epilepsy 16,17 .
however , neurological features were also identified in patients with nonsyndromic forms of pndm and tndm who carried kcnj11 mutations as speech delay , autistic spectrum disorder , and learning disability .
until now it is difficult to assure whether these complications are a consequence of the mutation or whether environmental and/or other genetic factors are involved 6 . in the case herein reported , the infant exhibited axial hypotonia and weak suction reflex , that may be caused by the mutation or / and may be due to exposure to hyperglycemia and ketosis during the first days of the child 's life 1,3,18 .
further studies are necessary to clarify the etiology of neurological impairment in tndm patients who carried kcnj11 mutations and to access the effectiveness of su in improving the neurological development . in conclusion
molecular diagnosis should be performed in order to identify those patients who may benefit from su therapy .
further investigation is required to understand clinical heterogeneity and the incomplete co - segregation of the kcnj11 mutation with diabetes , and also the molecular mechanisms underlying the biphasic course of tndm .

Answer:
key clinical messageneonatal diabetes is a monogenic form of diabetes .
 herein , we report on a newborn presenting diabetic ketoacidosis at 17 days of life .
 a kcnj11 mutation was identified . in such cases ,
 insulin can be replaced by sulfonylurea with a successful metabolic control , as an example of how molecular diagnosis may influence the clinical management of the disorder .


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:
though limited in efficacy in many cases , the control methods available today represent a major progress when compared to the lack of any means for the control of these plants one or two decades ago .
crops can be protected by resistance , by selective fungicides , by biocontrol agents , and by cultural methods that did not existed before . the current focus in applied
breeding is leveraging biotechnological tools to develop more and better markers to allow marker assisted selection with the hope that this will speed up the delivery of improved cultivars to the farmer . to date , however , progress in marker development and delivery of useful markers has been slow in legumes .
we are now also facing an accelerated progress in the genomic and biotechnological research , which should soon provide important understanding of some crucial developmental mechanisms in both the parasites and their host plants and will provide candidate genes for resistance to ascochyta blight .
the application of ngs technologies will provide a new research framework and molecular tools to be applied in resistance to ascochyta blight in legumes .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .

Answer:
legume cultivation is strongly hampered by the occurrence of ascochyta blights .
 strategies of control have been developed but only marginal successes achieved . breeding for disease resistance is regarded the most cost efficient method of control .
 significant genetic variation for disease resistance exists in most legume crops with numerous germplasm lines maintained , providing an excellent resource for plant breeders .
 fast and reliable screening methods have been adjusted to fulfill breeding program needs . however
 , the complex inheritance controlled quantitatively by multiple genes , has been difficult to manipulate .
 successful application of biotechnology to ascochyta blight resistance breeding in legume crops will facilitate a good biological knowledge both of the crops  pathogen interaction and of the mechanisms underlying resistance .
 the current focus in applied breeding is leveraging biotechnological tools to develop more and better markers to speed up the delivery of improved cultivars to the farmer . to date , however , progress in marker development and delivery of useful markers has been slow in most legumes .
 the limited saturation of the genomic regions bearing putative qtls in legume crops makes difficult to identify the most tightly linked markers and to determine the accurate position of qtls .
 the application of next generation sequencing technologies will contribute to the development of new markers and the identification of candidate genes for ascochyta blight resistance .


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

Paper text:
congenital adrenal hyperplasia ( cah ) is caused by deficiency of 21-hydroxylase in the
 adrenal glands .
cortisone acetate ( ca ) is used worldwide as an equivalent to hydrocortisone
 ( hc ) , as the glucocorticoid component of substitution therapy for cah .
hc is identical to cortisol , while ca is
 nearly equivalent to cortisone apart from the presence of an acetate group at the c21
 position .
cortisol represents active glucocorticoid , while cortisone is an inactive form .
 the hepatic enzyme 11-hydroxysteroid dehydrogenase
 ( 11-hsd ) type 1 catalyzes the conversion of cortisone to cortisol by
 reducing the keto group at the c11 position to a hydroxyl group
accordingly , orally
 administered ca must be converted to cortisol by 11-hsd in order to be
 bioactive .
the overall bioactivity of ca given orally has been reported to be 80% of that of hc ( 1 ) .
furthermore , a patient with 21-hydroxylase deficiency has been reported as
 a poor responder to ca treatment ( 2 ) .
we converted 10
 of our cah patients from ca to hc substitution therapy , compared clinical and laboratory
 findings before and after the change .
ten patients with cah caused by 21-hydroxylase deficiency were studied ( 6 male , 4 female ;
 ages , 4 to 35 yr ) .
of the 10 patients , 8 were salt
 losers , who required fludrocortisone in addition to glucocorticoids .
for all subjects , hc
 was administered instead of ca , initially at 80% of the previous ca dose .
the dose of hc
 then was increased or decreased according to circulating concentrations of
 17-hydroxyprogesterone ( ohp ) and/or adrenocorticotropin ( acth ) .
target concentrations were
 below 10 ng / ml for 17-ohp and below 50 pg / ml for acth .
doses of fludrocortisone were not
 changed . to compare required doses of ca and hc ,
the ca requirement was calculated as the
 average of the several months preceding the change of drug , while the hc requirement was the
 dose found to provide stable control of cah after several months .
these doses were
 calculated as milligrams per square meter of body - surface area . before and after the drug change , we measured concentrations of 17-ohp and acth , as well as
 patients height and weight . the mean observation period after the drug change was 10 mo ( 6
 to 14 mo ) .
a radioimmunoassay was used to measure 17-ohp , while acth was measured by
 immunoradiometric assay .
genomic dna of a patient who responded poorly to treatment with ca was obtained from
 peripheral leukocytes .
all exons , exon - intron boundary regions and 2.4 kb of the promoter
 region of 11-hsd were amplified by pcr .
then the dna sequence was
 determined using an abi prism 310 genetic analyzer . for bone age determination ,
the
 tanner - whitehouse 2 rus method according to the japanese standard was used .
the mean 17-ohp concentration during treatment of our patients with ca was 48.6 ng / ml . this
 decreased to 10.1 ng / ml when the treatment was changed to hc ( table 1table 1 demographic , pharmacologic , and endocrinologic data for individual
 subjects , fig .
1 serum concentrations of 17-hydroxyprogesterone ( ohp ) during treatment were
 significantly lowered by changing from cortisone acetate ( ca ) to hydrocortisone ( hc ) .

each data point represents the mean concentration of 17-ohp of an individual during
 treatment with ca or hc . ) .
the mean concentration of acth was 198.0 pg / ml during treatment with ca , decreasing
 to 35.1 pg / ml during treatment with hc .
we compared the dose of ca preceding the change of
 drug with that of hc after dose adjustment , when disease control was stable .
the average
 drug requirement for ca was 33.9 mg / m , while it was 20.3 mg / m for
 hc . the relationship can be expressed as an equation , hc = 0.58  ca , and the coefficient is
 substantially lower than the conventionally reported dose ratio of 0.8 ( 1 ) .
in addition ,
 older patients required more ca per square meter of body - surface than younger patients .
the
 relationship between the ca dose shortly before the change of drug and the final hc dose is
 shown in fig .
. 2 relationship between the dose requirements of cortisone acetate ( ca ) and
 hydrocortisone ( hc ) . the solid regression line can be expressed as : hc = 0.58
 ca .. no significant change in the obesity index occurred in any subject in association
 with the change of drug . among subjects who already had attained their adult height , all
 male patients ( cases 5 , 8 , and 9 ) showed short stature attributable to precocious puberty .
 in case 5 ,
four patients ( cases 1 to 4 ) who had been diagnosed by
 neonatal screening were at a prepubertal age . in cases 1 to 3 , no change of height sd score
 was recognized before or after the drug change .
case 4 showed some auxological change
 related to medication , described below .   serum concentrations of 17-hydroxyprogesterone ( ohp ) during treatment were
 significantly lowered by changing from cortisone acetate ( ca ) to hydrocortisone ( hc ) .

each data point represents the mean concentration of 17-ohp of an individual during
 treatment with ca or hc .
relationship between the dose requirements of cortisone acetate ( ca ) and
 hydrocortisone ( hc ) .
the solid regression line can be expressed as : hc = 0.58
 ca .
case 4 : a 10-yr - old boy was found to have an increased concentration of 17-ohp at 6 yr of
 age , and was treated with ca .
the ca dose was increased from 20 mg / m at 6 yr to
 35 mg / m at 8.2 yr . during this period ,
height velocity increased , as did height
 sd score ( 0.1 to 0.8 ) . the bone age ( ba ) / chronological age ( ca ) ratio also increased ( 0.9
 to 1.2 ) .
after conversion to hc at 9.4 yr of age , control of disease improved as evidenced
 by a decrease in 17-ohp . at 10.1 yr of age ,
the height sd score had decreased to 0.6 , and
 the ba / ca ratio had decreased to 1.1 . the hc requirement was 20.9 mg / m . in case 5 , we performed dna sequence analysis for 11-hsd type 1 because
 treatment with ca had no effect at all .
case 5 : a 13 -yr - old boy was referred from another hospital where he had been treated with
 28 mg / m of hc . in our outpatient clinic , treatment was changed to 36
 mg / m of ca . soon afterwards 17-ohp
increased abruptly to 260 ng / ml from 5.3
 ng / ml . the plasma level of acth increased to 1038 pg / ml from 8.3 pg / ml . since this patient
 appeared to be a poor responder to ca , 28 mg / m of hc
inability to respond to ca initially was thought to result from impaired
 low conversion of cortisone to cortisol , because of low activity of 11-hsd
 type 1 . however , dna sequence determination in the gene encoding this enzyme detected no
 changes from the reported normal sequence in any of the six exons , exon - intron boundary
 regions , or the promoter region ( 2.4 kb ) ( 3 ) .
in 10 patients with 21-hydroxylase deficiency , we changed the glucocorticoid for the
 substitution therapy from ca to hc .
indices of control of cah such as 17-ohp , and acth
 decreased , indicating improvement . on average , the final requirement for hc based on these
 indicators , was only 0.58 times the previous dose of ca , which was smaller than previously
 reported ( 1 ) .
whorwood and warne ( 4 ) determined urinary tetrahydrocortisone ( the ) /
 tetrahydrocortisol ( thf ) ratios for 14 cah patients treated with ca , and found that better
 control of the disease was associated with lower the / thf ratios .
the pharmacologic effect of ca depends on conversion of cortisone to cortisol by
 11-hsd .
however , when we performed gene sequencing in one of our poor ca
 responders , we found no mutation in the 11-hsd gene including the promoter
 region .
( 2 )
 similarly reported failure to detect a mutation in the 11-hsd gene .
up to
 the present , no 11-hsd gene mutation has been detected in poor responders .

even single - nucleotide polymorphism has not been common , apart from the recently reported
 intronic gene polymorphism ( 5 ) .
as described for case
 4 , an individual patient s response to ca can vary with age or other factors .
in addition ,
 blood concentrations of cortisone have been reported to be higher than those of cortisol in
 the neonatal period and early infancy ( 6 ) .
accordingly
 steroid metabolism in young children may differ from that in school - age or older children .
 in our study ,
a poor response
 to ca , therefore , may involve variability of 11-hsd activity rather than
 genetic changes .
jamieson et al . ( 7 ) reported a 36-yr - old woman who had clinical features of hypercortisolemia
 associated with a normal plasma cortisol concentration and an elevated urinary the / thf
 ratio , possibly caused by a defect in hepatic 11-hsd . in another case of 6

yr old boy with precocious pubarche had an elevated urinary the / thf ratio ( decreased thf / the
 ratio ) attributed to low activity of 11-hsd ( 8) . this enzyme has attracted considerable attention in studies concerning obesity and other
 endocrinological disorders .
an agonist at the peroxisome proliferator - activated receptor is
 suspected to regulate 11-hsd , decreasing its activity ( 9 ) . among patients with cah , good responders
however , we found no relationship between
 response to ca and obesity . among our subjects who attained adult height ,
male patients were shorter than previously
 reported adult patients with cah ( 10 ) .
our findings provided no definitive
 indication of whether or not hc is superior to ca in achieving a desirable height .
however ,
 in one growing child ( case 4 ) , changing the drug from ca to hc decreased the ba / ca ratio .

final height in patients treated with hc might prove to be greater than that in patients
 treated with ca .
as a therapeutic agent , ca shows considerably greater inter- and intra - individual
 variations in efficacy than hc .
in addition , we found greater difference in pharmacological
 activity between ca and hc than has been previously reported .
ca would seem inadequate for substitution
 therapy not only in patients with cah , but also those with other forms of adrenal
 insufficiency such as adrenal hypoplasia or hypofunction caused by pituitary disorders .

treatment with hc is recommended for these patients as well . however , since hc has been
 reported to be too bioavailable to maintain cortisol concentrations within physiologic
 limits ( 11 ) , careful evaluation of physiologic
 aspects of hc - based substitution regimens may be needed .

Answer:
although cortisone acetate is approved worldwide as corticosteroid substitution
 therapy in congenital adrenal hyperplasia ( 21-hydroxylase deficiency ) , its effectiveness
 is uncertain since its biologic activity depends on activation by
 11-hydroxysteroid dehydrogenase ( 11-hsd ) .
 we sought to
 compare the effect of cortisone acetate with that of hydrocortisone . in 10 patients with
 congenital adrenal hyperplasia ,
 cortisone acetate was replaced with hydrocortisone in
 substitution therapy . during this change ,
 blood concentrations of 17-hydroxy - progesterone ,
 adrenocorticotropin ( acth ) , and requirements for each drug were monitored .
 concentrations
 of 17-hydroxyprogesterone decreased ( mean 10.1 vs. 48.6 ng / ml ) , as did those of acth .

 cortisone acetate dose requirements averaged 33.9 mg / m2 , while hydrocortisone
 dose requirements averaged only 20.3 mg / m2 .
 in one of the patients resistant to
 cortisone acetate therapy , dna sequences in the coding regions and promoter of the
 11-hsd gene were analyzed , detecting no genetic abnormalities .

 cortisone acetate is inferior to hydrocortisone as substitution therapy in patients with
 congenital adrenal hyperplasia .