Speciality
Spotlight

 




 


Genetics


    

 




  • G.H. Sakorafas and A.G. Tsiotou [ Department of Surgery, 251 Hellenic Air Force Hospital, Messogion and Katehaki, Athens 115 25, Greece

    Genetic Predisposition to Breast Cancer : A Surgical Perspective

    Br. J. of Sur., Volume 87, Number 2, February, 2000, Pg. 149

         

    Molecular alterations in proto-oncogenes, tumour suppressor genes, and genes that function in DNA damage recognition and repair are considered to be the hallmarks of a carcinogenic process, including breast carcinogenesis.

        

    After a thorough review of literature the authors postulate that hereditary breast cancer accounts for 5-10 per cent of all breast cancer cases. About 90% of hereditary breast cancer involve mutation of BRCA1 and/or BRCA2 genes. Other cancer related genes [ myc, c-erbB2, Tsg101 and Mdgi] are involved in breast carcinogenesis, but they do not give rise to familial breast cancer syndromes. Risk estimation is the most important clinical implication. Management options for the high-risk mutation carriers include cancer surveillance and preventive strategies [prophylactic surgery or chemoprevention].

        

    They conclude that despite inadequate knowledge about the genetic predisposition to breast cancer and its clinical implications, the demand for genetic testing is likely to increase. In addition to risk estimation, cancer surveillance and preventive strategies, gene therapy offers a new and theoretically attractive approach to breast cancer management.

        

  • J.E. Creighton, R. Lyall, D.I. Wilson, A. Curtis and R.M. Charnley [Hepatopancreaticobiliary Surgery Unit, Freeman Hospital, Department of Human Genetics, Northern Region Genetics Service, Royal Victoria Infirmary, and Department of Human Genetics and Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK

    Mutations of the Cationic Trypsinogen Gene in Patients with Hereditary Pancreatitis

    Br.J. of Sur. Volume 87, Number 2, `February 2000, Pg. 170

         

    Hereditary pancreatitis has been known to be caused by one of two mutations [ R117H and N211] of the cationic trypsinogen gene [ PRSS1]. Families with hereditary pancreatitis were investigated for these mutations.

         

    In individuals from nine families with the diseases, DNA was screened for the R117H and N21I mutation. All five exons of the cationic trypsinogen gene were also sequenced to search for additional mutations. Haplotype analysis was carried out to identify common ancestors.

        

    The R117H mutation was identified in three families and the N21I in further five The R117H mutation was associated with a more severe phenotype than N211 in terms of mean [s.d.] age of onset of symptoms [8.4[7.2] versus 16.5[7.1] years; p=0.007] and requirement for surgical intervention [8 of 12 versus 4 of 17 respectively p= 0.029]. Haplotype analysis suggested that each mutation had arisen more than once.

        

  • V.L. Wills, J.O. Jorgensen and D. R. Hunt

    St George Upper Gastrointestinal Surgical Unit, Sydney, New South Wales, Australia

    Role of Relaparoscopy in the Management of Minor Bile Leakage After Laparoscopic Cholecystectomy

    Br.J. of Sur. Volume 87, Number 2, February 2000, Pg. 176

        

    Bile leakage in the absence of major ductal injury may occur from the liver bed or from the cystic duct remnant after cholecystectomy. The early limitations of minimally invasive surgery led to reliance on endoscopic methods to manage this complication. However, repeat laparoscopy permits drainage of the bile collection and direct control of the site of leakage in selected situations.

        

    15 cases of bile leakage [ of 1779 laparoscopic cholecystectomies i.e. 0.8% ] were studied. Two patients had spontaneous resolution. Ten patients with a subvesical duct leak had repeat laparoscopy. The leak was successfully controlled in 8 out of 10 patients by suturing and by a drain. One patient required a subsequent laparotomy for a localized pelvic collection. Three patients had cystic duct stump leakage. This was successfully managed by laparoscopy in one case but required endoscopic management in two.

        

    They conclude that laparoscopy is useful in the management of minor bile leaks after laparoscopic cholecystectomy . Selection of appropriate patients relies on a characteristic clinical presentation after an otherwise uncomplicated
    cholecystectomy.

        

  • F Fugt, MP Varyas, Z Zhaung, et al (NIH, Bethesda, Md)

    Utilisation of Molecular Genetics in the differentiation Between Adrenal cortical Adenomas and Carcinomas.

    Hum Pathol 28: 518-521, 1998.

        

    Background : With current advanced radiological techniques, small adrenal cortical lesions may be identified that are prone to misidentification.

        

    Expression of P53, P16 and other tumor suppressor genes was compared in hyperplasia, adenomas and carcinomas.

        

    Methods : Specific areas of each histologic slide were microdissected and subjected to polymerase chain reaction (PCR)for loss of heterozygosity (LOH) of 5 different tumor suppressor gene loci as follow

       

    1. P53 gene at chromosome 17p,

    2. P16 gene at chromosome 9p

    3. The neuroblastoma gene at 1p

    4. Von Hippel Lindav gene at chrom. 3p

    5. Retinoblastoma gene at 13q

       

    Results: None of the hyperplasias or adenomas showed LOH.

    – 61% of adrenocortical carcinomas showed genetic alterations for at least 1 of the markers.

    LOH of P53 was seen in 44%

    1P was seen in 22%

    3P was seen in 22%

    9p was seen in 26%

    80% of informative cases showed LOH of the retinoblastoma gene.

         

    Conclusions : The most informative markers for adrenal malignancy are P53 and 13q.

       

  • Samaras K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp, London; St. Vincent’s Hosp, Darlinghurst, New South Wales, Australia)

    Genetic and Envirnomental Influences on Total-Body and Central Abdominal Fat: The Effect of Physical Activity in Female Twins

    Ann Intern Med 130: 873-882,1 999

        

    Methods: Nine hundred seventy healthy female twins, aged 39 to 70 years were studied. Two hundred forty-one pairs were monozygotic, and 228 were dizygotic. Fifty six percent of the women were of normal weight, 30% were overweight, 7% were obese, and 7% were underweight.

       

    Conclusions – For healthy middle-aged women, current physical activity predicts lower total-body and central abdominal adiposity. After adjustments for genetic and environmental variables, the effects of physical activity are greater than those of other measured environmental factors.

        

    Editorial comments: This article shows the potentially powerful effects of regular physical activity in preventing increases in central obesity. The accumulation of central body fat has been shown to be a powerful predictor of type 2 diabetes and cardiovascular disease. 

        

  • Recently there has been a lot of emphasis on genetic factors and obesity. Editor E.T. Poehlman has selected number of articles from the literature and grouped together to underscore that the susceptibility to obesity and obesity-related phenotypes may be partially explained by genetic polymorphisms involved in the regulation of energy expenditure, substrate metabolism, and body composition. 

         


    The work of Heinonen et al (Univ of Turku, Finland; Univ Hosp of Helsinki; Unvi of Kuopio, Finland)
    Identification of a Three-Amino Acid Deletion in the a2B-Adrenergic Receptor That is Associated with Reduced Basal Metabolic Rate in Obese Subjects published in J Clin Endocrinol Metab 84: 2429-2433, 1999, elegantly shows that a genetic polymorphism of the a2B subtype can partly explain the reduced resting metabolic rate in obese individuals. A low resting metabolic rate may predict subsequent weight gain because of its large contribution to daily energy expenditure. 

         


    The work by Ishiyama-Shigemoto et al (Kurume Univ, Japan)
    Association of Polymorphisms in the b2-Adrenergic Receptor Gene with Obesity, Hypertriglyceridaemia, and Diabetes
    Mellitus
    , published in Diabetologia 42:98-101, 1999, supports the notion that the amino-terminal polymorphisms of the b2-adrenergic receptor gene could be involved in the pathogenesis of obesity and hypertriglyceridemia.

          


    The article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere, Finland; Univ of Kuopio, Finland)
    Additive Effects of the Mutations in the B3-Adrenergic Receptor and Uncoupling Protein-1 Genes on Weight Loss and Weight Maintenance in Finnish
    Women
    , published in J Clin Endocrinol Metab 83: 4246-4250, 1998, is particularly interesting. Its strength lies in the examination of various genetic variants to achieve successful weight loss and maintain a reduced body weight. This article specifically examined whether the simultaneous presence of the Trp64Arg mutation in the B3-adrenergic receptor and the A®G mutation in the uncoupling protein (UCP-1) gene have associations with weight loss and subsequent weight maintenance. The finding that the individuals with both mutations had a lower weight reduction and gained weight back more rapidly raises new questions regarding the polygenetic nature of obesity and the search for genes that may predict differential response to weight reduction programs.

            

  • K A Eddleman, JL Stone et al (New York,)

    Chorionic villus sampling before multifetal pregnancy reduction.

    Am J Obstet Gynecol, Nov.2000; 183: 1078-81




    Objective: This study was undertaken to determine the technical feasibility and accuracy of chorionic villus sampling before multifetal pregnancy reduction and to determine whether sampling increases the pregnancy loss rate after the reduction procedure.



    Study Design: Between January 22, 1986, and January 20, 2000, a total of 1183 patients underwent first-trimester multifetal pregnancy reduction at Mount Sinai Medical Center,Chorionic villus sampling was attempted in 86 patients before the reduction procedure. Information on the technical success and accuracy of chorionic villus sampling, as well as pregnancy outcome, was collected on all patients. Pregnancy loss rates before 24 weeks’ gestation in patients undergoing chorionic villus sampling before multifetal pregnancy reduction were compared with rates in patients not undergoing sampling.



    Results: chorionic villus sampling was successfully completed in 85 (98.8%) of 86 patients in whom sampling was attempted. Of 166 fetuses, 165 (99.4%) were successfully sampled. Of 165 fetuses, 3 (1.8%) had karyotypic abnormalities. Sampling errors were probably made in 2 (1.2%) of 165 fetuses. Of the 73 patients who have been delivered or are beyond 24 weeks’ gestation, only 1 patients (1.4%) had a pregnancy loss after the multifetal pregnancy reduction.



    Conclusion: Chorionic villus sampling before multifetal pregnancy reduction is technically feasible and accurate, with an acceptably low sampling error rate. Chorionic villus sampling before multifetal pregnancy reduction appears to be safe and does not increase the risk of loss after the reduction procedure.



    Comment: Authors suggest that in the presence of antenatal twin discordance HC/AC asymmetry may be a useful marker for identifying twin pregnancies at particular risk of perinatal morbidity and death.

  • R O Bahado-Singh, S Shahabi, M J Mahoney (New Haven, Connecticut)

    Comparison of urinary hyperglycosylated human chorionic gonadotropin concentration with the serum triple screen for Down syndrome detection in high-risk pregnancies.


    Am J Obstet Gynecol, Nov.2000; 183: 1114-8.



    Objective: Both modest screening performance and declining patient and physician acceptance have stimulated interest in alternative markers to the triple screen for the detection of Down syndrome. Authors purpose was to compare the concentration of a single urinary analyte, hyperglycosylated human chorionic gonadotropin, with the serum triple screen (a-fetoprotein, human chorionic gonadotropin, and unconjugated estriol concentrations combined with age) for second-trimester Down syndrome detection.



    Study Design: Urine and blood were obtained from pregnant women in the second trimester undergoing genetic amniocentesis. Urinary hyperglycosylated human chorionic gonadotropin concentration and serum triple-screen values were measured. Individuals undergoing amniocentesis because of abnormal triple screen results were excluded. Individual Down syndrome risks on the basis of urinary hyperglycosylated human chorionic gonadotropin concentration plus maternal age and on the basis of the triple-screen results were calculated. 



    For each algorithm the sensitivity and false-positive rate for Down syndrome detection at different risk thresholds were determined. From these values receiver operating characteristic curves were constructed, and the area under the curve was determined for each algorithm. Finally, the performance of a new combination in which urinary hyperglycosylated human chorionic gonadotropin concentration replaced serum human chorionic gonadotropin concentration in the triple screen was ascertained.



    Conclusion: The performance of urinary hyperglycosylated human chorionic gonadotropin concentration was statistically superior to that of the serum triple screen in a high-risk population. The use of urinary hyperglycosylated human chorionic gonadotropin concentration as an alternative test or substitution of this measurement for serum human chorionic gonadotropin concentration in the triple screen would improve diagnostic accuracy and address many current concerns related to the triple screen.

         

  • Kathryn Senior 

    A Molecular Mechanism For Thrombotic Thrombocytopenic Purpura 

    Lancet, Vol.358, October 6, 2001, Pg. 1162

          


    Summary: Researchers in USA have shown that mutations in the ADAMTS 13 gene are responsible for the familial form of thrombotic thrombocytopenic purpura (TTP). Missense mutations in the gene reduce the amount of active protease available to cleave the blood protein von Willebrand factor (VWF); large multimeric forms of VWF have been observed in the plasma of patients with TTP and are proposed to have a pathogenic role in the disease. 

        


    It is predicted that specific DNA diagnosis for patients with the relatively rare hereditary form of TTP could now be developed and it should now be possible to manufacture recombinant ADAMTS 13. 

         


    Potentially this would be safer for patients than plasma exchange as it would eliminate all risk of disease transfer through natural blood products. Understanding the biological function of ADAMTS 13 and the pathophysiology of TTP may lead to other novel approaches to therapy, not only for TTP but potentially for other bleeding and clotting
    disorders.

           

  • D. P. Wade and J. S. Owen 

    Regulation of the Cholesterol Efflux Gene, ABCA1

    Lancet Vol.357, January 20, 2001, Pg. 161-163

           

    Summary: The possibility of controlling serum LDL cholesterol concentrations with statins is a major advance. But statins are not very effective if dietary cholesterol intake is excessive and they do not rectify low HDL, a risk factor as important as raised LDL for coronary heart disease. So, drugs that raise HDL or impair dietary cholesterol uptake are needed.

           

    Recent discovery suggests that a single protein ABCA1 has key functions in HDL production and cholesterol absorption. The first breakthrough was identification of ABCA1 as the defective gene in Tangier disease, a rare disorder characterised by very low plasma HDL and an inability of cells to excrete cholesterol onto lipid-poor apoA-I, the main HDL precursor.

           

    ABCA1 protein belongs to a superfamily of membrane transporters that bind and hydrolyse ATP to drive diverse substrates across membranes. Cholesterol, and perhaps phospholipid are ABCA1 substrates and their efflux may be aided by binding of apoA-1 to ABCA1.

           

    This step, first stage in reverse cholesterol transport, enables peripheral cells to unload superfluous cholesterol onto HDL for transfer to liver.

          

    Can ABCA1 be upregulated, as a means of atheroprotection? ABCA1 activity can be increased by increasing transcription of the ABCA1 gene. Increase in ABCA1 expression is mediated by 2 members of nuclear receptor superfamily – LXR (liver X receptor) and RXR (retinol X receptor).

          

    Insights into potential benefits of upregulating ABCA1 expression will prompt increased efforts to uncover regulatory pathways that provide new targets for pharmacological intervention.

          

 



 

 

Speciality Spotlight

 

 
Genetics
    

 

  • G.H. Sakorafas and A.G. Tsiotou [ Department of Surgery, 251 Hellenic Air Force Hospital, Messogion and Katehaki, Athens 115 25, Greece
    Genetic Predisposition to Breast Cancer : A Surgical Perspective
    Br. J. of Sur., Volume 87, Number 2, February, 2000, Pg. 149
         
    Molecular alterations in proto-oncogenes, tumour suppressor genes, and genes that function in DNA damage recognition and repair are considered to be the hallmarks of a carcinogenic process, including breast carcinogenesis.
        
    After a thorough review of literature the authors postulate that hereditary breast cancer accounts for 5-10 per cent of all breast cancer cases. About 90% of hereditary breast cancer involve mutation of BRCA1 and/or BRCA2 genes. Other cancer related genes [ myc, c-erbB2, Tsg101 and Mdgi] are involved in breast carcinogenesis, but they do not give rise to familial breast cancer syndromes. Risk estimation is the most important clinical implication. Management options for the high-risk mutation carriers include cancer surveillance and preventive strategies [prophylactic surgery or chemoprevention].
        
    They conclude that despite inadequate knowledge about the genetic predisposition to breast cancer and its clinical implications, the demand for genetic testing is likely to increase. In addition to risk estimation, cancer surveillance and preventive strategies, gene therapy offers a new and theoretically attractive approach to breast cancer management.
        

  • J.E. Creighton, R. Lyall, D.I. Wilson, A. Curtis and R.M. Charnley [Hepatopancreaticobiliary Surgery Unit, Freeman Hospital, Department of Human Genetics, Northern Region Genetics Service, Royal Victoria Infirmary, and Department of Human Genetics and Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK
    Mutations of the Cationic Trypsinogen Gene in Patients with Hereditary Pancreatitis
    Br.J. of Sur. Volume 87, Number 2, `February 2000, Pg. 170
         
    Hereditary pancreatitis has been known to be caused by one of two mutations [ R117H and N211] of the cationic trypsinogen gene [ PRSS1]. Families with hereditary pancreatitis were investigated for these mutations.
         
    In individuals from nine families with the diseases, DNA was screened for the R117H and N21I mutation. All five exons of the cationic trypsinogen gene were also sequenced to search for additional mutations. Haplotype analysis was carried out to identify common ancestors.
        
    The R117H mutation was identified in three families and the N21I in further five The R117H mutation was associated with a more severe phenotype than N211 in terms of mean [s.d.] age of onset of symptoms [8.4[7.2] versus 16.5[7.1] years; p=0.007] and requirement for surgical intervention [8 of 12 versus 4 of 17 respectively p= 0.029]. Haplotype analysis suggested that each mutation had arisen more than once.
        

  • V.L. Wills, J.O. Jorgensen and D. R. Hunt
    St George Upper Gastrointestinal Surgical Unit, Sydney, New South Wales, Australia
    Role of Relaparoscopy in the Management of Minor Bile Leakage After Laparoscopic Cholecystectomy
    Br.J. of Sur. Volume 87, Number 2, February 2000, Pg. 176
        
    Bile leakage in the absence of major ductal injury may occur from the liver bed or from the cystic duct remnant after cholecystectomy. The early limitations of minimally invasive surgery led to reliance on endoscopic methods to manage this complication. However, repeat laparoscopy permits drainage of the bile collection and direct control of the site of leakage in selected situations.
        
    15 cases of bile leakage [ of 1779 laparoscopic cholecystectomies i.e. 0.8% ] were studied. Two patients had spontaneous resolution. Ten patients with a subvesical duct leak had repeat laparoscopy. The leak was successfully controlled in 8 out of 10 patients by suturing and by a drain. One patient required a subsequent laparotomy for a localized pelvic collection. Three patients had cystic duct stump leakage. This was successfully managed by laparoscopy in one case but required endoscopic management in two.
        
    They conclude that laparoscopy is useful in the management of minor bile leaks after laparoscopic cholecystectomy . Selection of appropriate patients relies on a characteristic clinical presentation after an otherwise uncomplicated cholecystectomy.
        

  • F Fugt, MP Varyas, Z Zhaung, et al (NIH, Bethesda, Md)
    Utilisation of Molecular Genetics in the differentiation Between Adrenal cortical Adenomas and Carcinomas.
    Hum Pathol 28: 518-521, 1998.
        
    Background : With current advanced radiological techniques, small adrenal cortical lesions may be identified that are prone to misidentification.
        
    Expression of P53, P16 and other tumor suppressor genes was compared in hyperplasia, adenomas and carcinomas.
        
    Methods : Specific areas of each histologic slide were microdissected and subjected to polymerase chain reaction (PCR)for loss of heterozygosity (LOH) of 5 different tumor suppressor gene loci as follow
       
    1. P53 gene at chromosome 17p,
    2. P16 gene at chromosome 9p
    3. The neuroblastoma gene at 1p
    4. Von Hippel Lindav gene at chrom. 3p
    5. Retinoblastoma gene at 13q
       
    Results: None of the hyperplasias or adenomas showed LOH.
    – 61% of adrenocortical carcinomas showed genetic alterations for at least 1 of the markers.
    LOH of P53 was seen in 44%
    1P was seen in 22%
    3P was seen in 22%
    9p was seen in 26%
    80% of informative cases showed LOH of the retinoblastoma gene.
         
    Conclusions : The most informative markers for adrenal malignancy are P53 and 13q.
       

  • Samaras K, Kelly PJ, Chiano MN, et al (St Thomas’ Hosp, London; St. Vincent’s Hosp, Darlinghurst, New South Wales, Australia)
    Genetic and Envirnomental Influences on Total-Body and Central Abdominal Fat: The Effect of Physical Activity in Female Twins
    Ann Intern Med 130: 873-882,1 999
        
    Methods: Nine hundred seventy healthy female twins, aged 39 to 70 years were studied. Two hundred forty-one pairs were monozygotic, and 228 were dizygotic. Fifty six percent of the women were of normal weight, 30% were overweight, 7% were obese, and 7% were underweight.
       
    Conclusions – For healthy middle-aged women, current physical activity predicts lower total-body and central abdominal adiposity. After adjustments for genetic and environmental variables, the effects of physical activity are greater than those of other measured environmental factors.
        
    Editorial comments: This article shows the potentially powerful effects of regular physical activity in preventing increases in central obesity. The accumulation of central body fat has been shown to be a powerful predictor of type 2 diabetes and cardiovascular disease. 
        

  • Recently there has been a lot of emphasis on genetic factors and obesity. Editor E.T. Poehlman has selected number of articles from the literature and grouped together to underscore that the susceptibility to obesity and obesity-related phenotypes may be partially explained by genetic polymorphisms involved in the regulation of energy expenditure, substrate metabolism, and body composition. 
         
    The work of Heinonen et al (Univ of Turku, Finland; Univ Hosp of Helsinki; Unvi of Kuopio, Finland) Identification of a Three-Amino Acid Deletion in the a2B-Adrenergic Receptor That is Associated with Reduced Basal Metabolic Rate in Obese Subjects published in J Clin Endocrinol Metab 84: 2429-2433, 1999, elegantly shows that a genetic polymorphism of the a2B subtype can partly explain the reduced resting metabolic rate in obese individuals. A low resting metabolic rate may predict subsequent weight gain because of its large contribution to daily energy expenditure. 
         
    The work by Ishiyama-Shigemoto et al (Kurume Univ, Japan) Association of Polymorphisms in the b2-Adrenergic Receptor Gene with Obesity, Hypertriglyceridaemia, and Diabetes Mellitus, published in Diabetologia 42:98-101, 1999, supports the notion that the amino-terminal polymorphisms of the b2-adrenergic receptor gene could be involved in the pathogenesis of obesity and hypertriglyceridemia.
          
    The article by Fogelholm et al (UKK Inst for Health Promotion and Research, Tampere, Finland; Univ of Kuopio, Finland) Additive Effects of the Mutations in the B3-Adrenergic Receptor and Uncoupling Protein-1 Genes on Weight Loss and Weight Maintenance in Finnish Women, published in J Clin Endocrinol Metab 83: 4246-4250, 1998, is particularly interesting. Its strength lies in the examination of various genetic variants to achieve successful weight loss and maintain a reduced body weight. This article specifically examined whether the simultaneous presence of the Trp64Arg mutation in the B3-adrenergic receptor and the A®G mutation in the uncoupling protein (UCP-1) gene have associations with weight loss and subsequent weight maintenance. The finding that the individuals with both mutations had a lower weight reduction and gained weight back more rapidly raises new questions regarding the polygenetic nature of obesity and the search for genes that may predict differential response to weight reduction programs.
            

  • K A Eddleman, JL Stone et al (New York,)
    Chorionic villus sampling before multifetal pregnancy reduction.
    Am J Obstet Gynecol, Nov.2000; 183: 1078-81


    Objective: This study was undertaken to determine the technical feasibility and accuracy of chorionic villus sampling before multifetal pregnancy reduction and to determine whether sampling increases the pregnancy loss rate after the reduction procedure.

    Study Design: Between January 22, 1986, and January 20, 2000, a total of 1183 patients underwent first-trimester multifetal pregnancy reduction at Mount Sinai Medical Center,Chorionic villus sampling was attempted in 86 patients before the reduction procedure. Information on the technical success and accuracy of chorionic villus sampling, as well as pregnancy outcome, was collected on all patients. Pregnancy loss rates before 24 weeks’ gestation in patients undergoing chorionic villus sampling before multifetal pregnancy reduction were compared with rates in patients not undergoing sampling.

    Results: chorionic villus sampling was successfully completed in 85 (98.8%) of 86 patients in whom sampling was attempted. Of 166 fetuses, 165 (99.4%) were successfully sampled. Of 165 fetuses, 3 (1.8%) had karyotypic abnormalities. Sampling errors were probably made in 2 (1.2%) of 165 fetuses. Of the 73 patients who have been delivered or are beyond 24 weeks’ gestation, only 1 patients (1.4%) had a pregnancy loss after the multifetal pregnancy reduction.

    Conclusion: Chorionic villus sampling before multifetal pregnancy reduction is technically feasible and accurate, with an acceptably low sampling error rate. Chorionic villus sampling before multifetal pregnancy reduction appears to be safe and does not increase the risk of loss after the reduction procedure.

    Comment: Authors suggest that in the presence of antenatal twin discordance HC/AC asymmetry may be a useful marker for identifying twin pregnancies at particular risk of perinatal morbidity and death.

  • R O Bahado-Singh, S Shahabi, M J Mahoney (New Haven, Connecticut)
    Comparison of urinary hyperglycosylated human chorionic gonadotropin concentration with the serum triple screen for Down syndrome detection in high-risk pregnancies.
    Am J Obstet Gynecol, Nov.2000; 183: 1114-8.

    Objective: Both modest screening performance and declining patient and physician acceptance have stimulated interest in alternative markers to the triple screen for the detection of Down syndrome. Authors purpose was to compare the concentration of a single urinary analyte, hyperglycosylated human chorionic gonadotropin, with the serum triple screen (a-fetoprotein, human chorionic gonadotropin, and unconjugated estriol concentrations combined with age) for second-trimester Down syndrome detection.

    Study Design: Urine and blood were obtained from pregnant women in the second trimester undergoing genetic amniocentesis. Urinary hyperglycosylated human chorionic gonadotropin concentration and serum triple-screen values were measured. Individuals undergoing amniocentesis because of abnormal triple screen results were excluded. Individual Down syndrome risks on the basis of urinary hyperglycosylated human chorionic gonadotropin concentration plus maternal age and on the basis of the triple-screen results were calculated. 

    For each algorithm the sensitivity and false-positive rate for Down syndrome detection at different risk thresholds were determined. From these values receiver operating characteristic curves were constructed, and the area under the curve was determined for each algorithm. Finally, the performance of a new combination in which urinary hyperglycosylated human chorionic gonadotropin concentration replaced serum human chorionic gonadotropin concentration in the triple screen was ascertained.

    Conclusion: The performance of urinary hyperglycosylated human chorionic gonadotropin concentration was statistically superior to that of the serum triple screen in a high-risk population. The use of urinary hyperglycosylated human chorionic gonadotropin concentration as an alternative test or substitution of this measurement for serum human chorionic gonadotropin concentration in the triple screen would improve diagnostic accuracy and address many current concerns related to the triple screen.
         

  • Kathryn Senior 
    A Molecular Mechanism For Thrombotic Thrombocytopenic Purpura 
    Lancet, Vol.358, October 6, 2001, Pg. 1162
          
    Summary: Researchers in USA have shown that mutations in the ADAMTS 13 gene are responsible for the familial form of thrombotic thrombocytopenic purpura (TTP). Missense mutations in the gene reduce the amount of active protease available to cleave the blood protein von Willebrand factor (VWF); large multimeric forms of VWF have been observed in the plasma of patients with TTP and are proposed to have a pathogenic role in the disease. 
        
    It is predicted that specific DNA diagnosis for patients with the relatively rare hereditary form of TTP could now be developed and it should now be possible to manufacture recombinant ADAMTS 13. 
         
    Potentially this would be safer for patients than plasma exchange as it would eliminate all risk of disease transfer through natural blood products. Understanding the biological function of ADAMTS 13 and the pathophysiology of TTP may lead to other novel approaches to therapy, not only for TTP but potentially for other bleeding and clotting disorders.
           

  • D. P. Wade and J. S. Owen 
    Regulation of the Cholesterol Efflux Gene, ABCA1
    Lancet Vol.357, January 20, 2001, Pg. 161-163
           
    Summary: The possibility of controlling serum LDL cholesterol concentrations with statins is a major advance. But statins are not very effective if dietary cholesterol intake is excessive and they do not rectify low HDL, a risk factor as important as raised LDL for coronary heart disease. So, drugs that raise HDL or impair dietary cholesterol uptake are needed.
           
    Recent discovery suggests that a single protein ABCA1 has key functions in HDL production and cholesterol absorption. The first breakthrough was identification of ABCA1 as the defective gene in Tangier disease, a rare disorder characterised by very low plasma HDL and an inability of cells to excrete cholesterol onto lipid-poor apoA-I, the main HDL precursor.
           
    ABCA1 protein belongs to a superfamily of membrane transporters that bind and hydrolyse ATP to drive diverse substrates across membranes. Cholesterol, and perhaps phospholipid are ABCA1 substrates and their efflux may be aided by binding of apoA-1 to ABCA1.
           
    This step, first stage in reverse cholesterol transport, enables peripheral cells to unload superfluous cholesterol onto HDL for transfer to liver.
          
    Can ABCA1 be upregulated, as a means of atheroprotection? ABCA1 activity can be increased by increasing transcription of the ABCA1 gene. Increase in ABCA1 expression is mediated by 2 members of nuclear receptor superfamily – LXR (liver X receptor) and RXR (retinol X receptor).
          
    Insights into potential benefits of upregulating ABCA1 expression will prompt increased efforts to uncover regulatory pathways that provide new targets for pharmacological intervention.
          

 

 

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