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Re: Thrombophilias From: Fisher, Allan (AFisher@stpetershealthcare.org) Thu Apr 14 20:46:15 2005 Messages sorted by: [ date ][ thread ][ subject ][ author ] Next message: Stmidwife@aol.com: "Re: VBAC" Previous message: art fougner, md: "Re: VBAC" AFisher@stpetershealthcare.org of St.Peter's Health Care Services would like you to know: St. Peter's Begins Secure E-mail April 18: Starting Monday, April 18, 2005, St. Peter's Health Care Services will begin using a secure e-mail system to protect messages that contain patient information or other sensitive data. This helps us to comply with the national privacy law (HIPAA). For routine messages that lack such information, it will mean no change. However, messages that contain patient health or financial information will be automatically encrypted by the ZixMail system. Recipients at doctors' offices, HMOs and other non-St. Peter's organizations must click on a link and go to a secure Web site to retrieve the message. These users can easily establish a user ID and password at the secure site. More details available at: http://www.stpetershealthcare.org/SecureEmail/ Just FYI: You will see the significance in 4G/4G vs. 4G/5G vs 5G/5G alleles/polymorphisms in the text (underlined)- The observation to our particular interest is in green and underlined. PLASMINOGEN ACTIVATOR INHIBITOR 1; PAI1 Alternative titles; symbols PLANH1 SERPINE1 PLASMINOGEN ACTIVATOR INHIBITOR, BETA-MIGRATING ENDOTHELIAL-CELL-DERIVED TYPE, INCLUDED; PAIE, INCLUDED Gene map locus 7q21.3-q22 <http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?l173360> TEXT Ginsburg et al. (1986) <javascript:Anchor('173360_Reference11')> isolated a full-length cDNA corresponding to plasminogen activator inhibitor-1 (PAI1) from a human umbilical vein endothelial cell lambda gt11 cDNA library. By nucleotide sequence analysis, they found that the PAI1 cDNA encodes a protein containing 402 amino acids with a predicted nonglycosylated molecular mass of 45 kD. Cultured human umbilical vein endothelial cells contain 2 PAI1 mRNA species, both encoded by a single gene, differing by 1 kb in the 3-prime untranslated region. Plasminogen activator inhibitor shows structural similarities to angiotensinogen (106150), alpha-1-antitrypsin (107400), and antithrombin III (107300). Plasminogen activator inhibitor-2 is less similar to PAI1 than it is to the other proteins of this group. There are at least 3 immunologically distinct plasminogen activator inhibitors (PAIs): placental PAI, protease nexin, and endothelial-cell-derived PAI. The last is also distinctive for its beta-mobility in agarose zone electrophoresis and its inhibition of both tissue-type PA (173370) and urokinase-type PA (191840). 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Ny et al. (1986) <javascript:Anchor('173360_Reference24')> cloned and sequenced a cDNA for PAIE. The deduced amino acid sequence showed 30% homology with alpha-1-antitrypsin and antithrombin III, indicating that it is a member of the serine proteinase inhibitor (serpin) superfamily. In a genomic cosmid library, Loskutoff et al. (1987) <javascript:Anchor('173360_Reference20')> found 2 independent clones, each harboring the entire PLANH1 gene. Restriction site mapping, electron microscopic inspection of heteroduplexes, and nucleotide sequence analysis all demonstrated that the PLANH1 gene is approximately 12.2 kb pairs long and consists of 9 exons and 8 introns. Transcription of the PLANH1 gene in cultured vascular endothelial cells resulted in 2 distinct mRNA species. The data suggested that these 2 transcripts arose by alternative polyadenylation. Van Zonneveld et al. (1988) <javascript:Anchor('173360_Reference32')> isolated and sequenced the promoter of the PLANH1 gene. They used promoter-deletion mapping experiments and fusion of promoter fragments to a heterologous gene to show the existence of an enhancer-like glucocorticoid responsive element within the regions between nucleotides -305 and 75 of the PLANH1 gene. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Ginsburg et al. (1986) <javascript:Anchor('173360_Reference11')> assigned the PAI1 gene to human chromosome 7 by hybridization with sorted chromosomes. Klinger et al. (1987) <javascript:Anchor('173360_Reference16')> stated that the PAIE gene resides on 7q, about 3 cM from erythropoietin (133170) and the alpha-2 chain of type I collagen (120160), which are very tightly linked. It is between these loci and about 20 cM away from the cystic fibrosis locus (602421). By Southern blot analysis of a panel of human/mouse somatic cell hybrids, Klinger et al. (1987) <javascript:Anchor('173360_Reference16')> assigned the PAI1 gene to 7cen-q32; by in situ hybridization, they localized it to 7q21.3-q22. They also mapped its location in relation to other markers on chromosome 7 by means of family studies. Schwartz et al. (1991) <javascript:Anchor('173360_Reference31')> localized the PLANH1 gene to 7q22.1-q22.3 by study of an interstitial deletion. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Thrombophilia due to increased concentration of plasminogen activator inhibitor was described by Nilsson et al. (1985) <javascript:Anchor('173360_Reference22')> . Nilsson and Tengborn (1983) <javascript:Anchor('173360_Reference23')> restudied 2 members of a large family in which venous thrombosis was thought originally to have been associated with deficiency of plasminogen activator. After venous occlusion, both members of the family showed a normal release of tissue plasminogen activator antigen but low tissue plasminogen activator concentrations as measured by fibrin plates. Their plasma contained 50 times more tissue plasminogen activator inhibitor than normal. In an elderly patient with a history of lifelong severe bleeding after surgery or trauma and with evidence of persistent hyperfibrinolysis, Schleef et al. (1989) <javascript:Anchor('173360_Reference30')> found defective PAI1. They stated that this was the first demonstration of a relationship between decreased in vivo PAI1 activity and disordered hemostasis. Engesser et al. (1989) <javascript:Anchor('173360_Reference5')> was unable to establish a connection between familial thrombophilia and inherited, persistent elevation of plasma PAI. The cause-and-effect relationship between increased plasminogen activator inhibitor-1 and thrombosis is supported by the observations of Erickson et al. (1990) <javascript:Anchor('173360_Reference6')> who, from studies of mice transgenic for this gene, concluded that elevated levels contribute to the development of venous but not arterial occlusions. Patrassi et al. (1992) <javascript:Anchor('173360_Reference27')> presented a family with several presumably affected members. Glueck et al. (1993) <javascript:Anchor('173360_Reference12')> found familial high plasminogen activator inhibitor with hypofibrinolysis as the cause of osteonecrosis of both hips and a shoulder in a 29-year-old white male. High functional PAI and PAI antigen appeared to be inherited as an autoso mal dominant. They referred to other patients with idiopathic osteonecrosis and a high level of PAI. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> In a patient with PAI1 deficiency, Fay et al. (1992) <javascript:Anchor('173360_Reference9')> identified a homozygous frameshift mutation in the PAI1 gene. Fay et al. (1997) <javascript:Anchor('173360_Reference8')> reported a more comprehensive description of the phenotype associated with PAI1 deficiency; see 173360.0001. Carmeliet et al. (1997) <javascript:Anchor('173360_Reference2')> provided direct evidence to support a role for PAI1 in arterial wound healing. Techniques of arterial injury were designed in mice to model the histologic changes seen in human arteries following angioplasty and surgical anastomosis. PAI1 gene knockout mice underwent arterial injury followed by adenovirus-mediated PAI1 gene transfer by intravenous injection. Recombinant PAI1 expression was demonstrated in injured arteries and was found to inhibit neointima formation by inhibiting smooth muscle cell migration. Carmeliet et al. (1997) <javascript:Anchor('173360_Reference2')> suggested that this may have implications for the treatment of arterial stenosis in humans following surgical intervention. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> In a cross-sectional study of patients with a history of myocardial infarction (MI) and in matched controls from the Finnish population, Pastinen et al. (1998) <javascript:Anchor('173360_Reference26')> analyzed common variants of 8 genes implicated previously as risk factors for coronary heart disease or MI. The most common low density lipoprotein receptor (LDLR; 606945) mutations in Finland were also included in the analysis. Multiplex genotyping of the target genes was performed using a specific and efficient array-based minisequencing system. The 4G allele (173360.0002) of the PAI1 gene (P less than 0.05) and the Pl(A2) allele of the glycoprotein IIIa (ITGB3; 173470) gene (P less than 0.01) were associated with an increased risk of MI in the Finnish study population. They found that the combined effect of these risk alleles conferred a high risk for the development of MI (odds ratio (OR) = 4.5, P = 0.001), which was particularly prominent in male subjects (OR = 6.4, P = 0.0005). The observation of 2 separate genes contributing an additive risk of developing MI exemplified the advantages of multiplex analysis of genetic variation. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Kohler and Grant (2000) <javascript:Anchor('173360_Reference19')> discussed the mechanisms regulating the production and action of PAI1 and the role of gene-environment interactions in controlling fibrinolysis. They also discussed how these factors may affect the risk of artherothrombosis in persons with coronary artery disease. Halleux et al. (1999) <javascript:Anchor('173360_Reference13')> investigated the hormonal control of PAI1 gene expression and secretion in cultured human adipose tissue. They focused on the effects of glucocorticoids, insulin, cAMP, and catecholamines in explants from the omental region. The addition of dexamethasone to the culture medium increased PAI1 secretion in a time-dependent manner for up to 24 hours. The stimulation by the glucocorticoid was preceded by a 2-fold rise in PAI1 mRNA levels between 4 to 8 hours of culture. The authors concluded that there is reciprocal regulation of PAI1 by dexamethasone (positive effector) and cAMP/catecholamines (negative effectors) in cultured human adipose tissue. The stimulation by glucocorticoids could contribute to enhanced production of PAI1 by adipose tissue and high plasma levels of PAI1 associated with central obesity and thereby be a link between this disorder and cardiovascular disease. Impaired inhibition by catecholamines could also contribute, as in vivo adipose tissue responses to these hormones are usually blunted in obese individuals. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Crandall et al. (2000) <javascript:Anchor('173360_Reference3')> investigated the role of PAI1 in cultures of human preadipocytes from men and women of various ages and body mass indexes. Human preadipocytes expressed the mRNA for PAI1 and released significant quantities of PAI1 protein into the medium. As PAI1 regulates motility through the interaction of vitronectin with its receptor, the integrin alpha-V-beta-3 (see 193210), we identified this receptor in human preadipocytes. Transwells with active PAI1 prevented preadipocyte migration. Vitronectin was identified in homogenates of the stromal-vascular fraction of human adipose tissue, but was absent from human adipocytes and cultured preadipocytes. The authors concluded that human preadipocyte migration is regulated through the endogenous expression of PAI1 and alpha-V-beta-3 integrin, a novel autocrine mechanism for potentially regulating cell cluster formation in adipogenesis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Yamada et al. (2002) <javascript:Anchor('173360_Reference35')> performed a 2-stage association study of myocardial infarction using 112 polymorphisms of 71 candidate genes in 2,819 unrelated Japanese patients with myocardial infarction and 2,242 unrelated Japanese controls. In an initial screening in 909 of the subjects with myocardial infarction, 19 polymorphisms were selected in men and 18 in women, after adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4,152 subjects, similar logistic regression analysis revealed that the risk of myocardial infarction was significantly associated with the 1019C-T polymorphism in the connexin-37 gene (121012) in men and the 5A-1171/6A polymorphism in the stromelysin I gene (185250) and the 4G-668/5G polymorphism in the PAI1 gene in women. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Aldosterone enhances angiotensin II (see 106150)-induced PAI1 expression in vitro. Sawathiparnich et al. (2003) <javascript:Anchor('173360_Reference29')> tested the hypothesis that angiotensin II type 1 and aldosterone receptor (600983) antagonism interact to decrease PAI1 in humans. Effects of candesartan, spironolactone, or combined candesartan/spironolactone on mean arterial pressure, endocrine, and fibrinolytic variables were measured in 18 normotensive subjects in whom the renin (179820)-angiotensin-aldosterone system was activated by furosemide. This study evidenced an interactive effect of endogenous angiotensin II and aldosterone on PAI1 production in humans. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> ANIMAL MODEL Carbon monoxide can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase-1 (141250) in response to ischemic stress. Hmox1 -/- mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled carbon monoxide. Carbon monoxide drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of PAI1 in mononuclear phagocytes, which reduced accrual of microvascular fibrin. Carbon monoxide-mediated ischemic protection observed in wildtype mice was lost in PAI1-null mice. Fujita et al. (2001) <javascript:Anchor('173360_Reference10')> concluded that their data established a fundamental link between carbon monoxide and prevention of ischemic injury based on the ability of carbon monoxide to derepress the fibrinolytic axis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Yamamoto et al. (2002) <javascript:Anchor('173360_Reference36')> investigated the stress-induced changes in murine Pai1 gene expression to study the role of this inhibitor in the development of stress-induced hypercoagulability. Restraint stress led to a dramatic induction of plasma Pai1 antigen and of tissue Pai1 mRNA, with maximum induction in adipose tissues. In situ hybridization analysis of the stressed mice revealed that strong signals for Pai1 mRNA were localized to hepatocytes, renal tubular epithelial cells, adrenomedullar chromaffin cells, neural cells in the paraaortic sympathetic ganglion, vascular smooth muscle cells, and adipocytes, but not to endothelial cells. Thus, stress induced Pai1 gene expression in a tissue-specific and cell-specific manner. The induction of Pai1 mRNA by restraint stress was greater than that observed for heat shock protein (see 140550), a typical stress protein, suggesting that Pai1 is one of the most highly induced stress proteins. The magnitude of induction of Pai1 mRNA by stress increased markedly with age, and this increase in Pai1 correlated with tissue thrombosis in the older stressed mice. Moreover, much less tissue thrombosis was induced by restraint stress in young and aged Pai1-deficient mice compared with age-matched wildtype mice. These results suggested that the large induction of PAI1 by stress increases the risk for thrombosis in older populations, and that adipose tissue may be involved. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Boccaccio et al. (2005) <javascript:Anchor('173360_Reference1')> developed a mouse model of sporadic tumorigenesis in which they targeted the activated human MET oncogene (164860) to adult liver. They observed slowly progressive hepatocarcinogenesis, which was preceded and accompanied by a disseminated intravascular coagulation (DIC)-like thrombohemorrhagic syndrome. Genomewide expression profiling of MLP29 cells transduced with the activated MET oncogene revealed prominent upregulation of PAI1 and cyclooxygenase-2 (PTGS2; 600262), and in vivo administration of a PAI1 or COX2 inhibitor slowed the evolution towards full-blown DIC. Boccaccio et al. (2005) <javascript:Anchor('173360_Reference1')> concluded that this study provided the first direct genetic evidence for the link between oncogene activation and hemostasis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> ALLELIC VARIANTS (selected examples) .0001 PLASMINOGEN ACTIVATOR INHIBITOR 1 DEFICIENCY [PAI1, 2-BP INS, 4977TA] In a 9-year-old girl from an Old Order Amish community, Fay et al. (1992) <javascript:Anchor('173360_Reference9')> found homozygosity for a frameshift mutation: a dinucleotide (TA) insertion in exon 4 resulting in the synthesis of a truncated, nonfunctional protein. The TA insertion represented a duplication of nucleotides 4975 and 4976. The mature PAI1 protein has 379 amino acids. The mutation caused a shift in the reading frame after the codon for amino acid 210, resulting in a new stop codon (TGA) 45 codons into the aberrant reading frame. The predicted protein product lacked the 169 C-terminal amino acids of the wildtype protein, including the active center, arg346-met347. The proposita had had several episodes of major hemorrhage, all in response to trauma or surgery. Because of her young age, no conclusions could be drawn about the proposed role of PAI1 as a regulator of ovulation or tumor metastasis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Fay et al. (1997) <javascript:Anchor('173360_Reference8')> reported a more comprehensive description of the phenotype associated with PAI1 deficiency by identifying and characterizing multiple individuals in this pedigree that carried the mutation, and by following affected individuals for a prolonged period. They used allele-specific oligonucleotide hybridization to genotype individuals, and serum PAI1 antigen was measured by enzyme-linked immunosorbent assay. By this approach, they identified 19 individuals who were heterozygous for the null allele and 7 homozygotes with complete deficiency. Clinical manifestations were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygously affected individuals. They observed a spectrum of bleeding patterns, including intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including epsilon-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygotes. Heterozygotes did not display abnormal bleeding, even after trauma or surgery. The observations of Fay et al. (1997) <javascript:Anchor('173360_Reference8')> supported the hypothesis that the primary function of plasminogen activator inhibitor-1 in vivo is to regulate vascular fibrinolysis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> .0002 PLASMINOGEN ACTIVATOR INHIBITOR POLYMORPHISM [PAI1, 1-BP DEL/INS, 4G/5G] Dawson et al. (1993) <javascript:Anchor('173360_Reference4')> and Eriksson et al. (1995) <javascript:Anchor('173360_Reference7')> demonstrated that raised PAI1 plasma levels are related to a 1-bp guanine deletion/insertion (4G/5G) polymorphism in the promoter of the PAI1 gene. Evidence suggested that the plasma levels of PAI1 modulate the risk of coronary artery disease; furthermore, that the 4G/5G polymorphism affects the expression of the PAI1 gene. Margaglione et al. (1998) <javascript:Anchor('173360_Reference21')> investigated the relationship between the PAI1 4G/5G polymorphism in 1,179 healthy employees and the occurrence of coronary artery disease in their first-degree relatives. The group with a first-degree relative who had suffered from a coronary ischemic episode had a higher number of homozygotes for the deleted allele (4G/4G) of the PAI1 gene compared with subjects without such a family history (odds ratio = 1.62). The frequency of the 4G allele was abnormally high in these individuals as well. The individuals with a positive family history were older and exhibited a higher body mass index and total cholesterol levels than those without. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> In a study of the PAI1 genotype in 175 children with meningococcal disease, Hermans et al. (1999) <javascript:Anchor('173360_Reference15')> found that the median PAI1 concentration in children who died was substantially higher than that in survivors. Patients with the 4G/4G genotype had significantly higher PAI1 concentrations than those with the 4G/5G or 5G/5G genotype and had an increased risk of death. The findings suggested that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteremia or meningitis without septic shock. Westendorp et al. (1999) <javascript:Anchor('173360_Reference33')> investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock. They studied 50 patients who survived meningococcal infection, and 131 controls from the same geographic region. Because they had no information on genotypes of patients who died, they also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the PAI1 gene. The 4G allele was associated with increased gene transcription in cell lines in vitro and with increased PAI1 concentrations in carriers in vivo. The allele frequencies of 4G and 5G were similar between patients and controls. However, the 4G/4G genotype was present in only 9% of relatives of patients with meningitis compared with 36% of relatives of patients with septic shock. Patients whose relatives were carriers of the 4G/4G genotype had a 6-fold higher risk of developing septic shock than meningitis compared with all other genotypes. Westendorp et al. (1999) <javascript:Anchor('173360_Reference33')> concluded that variation in the PAI1 gene does not affect the probability of contracting meningococcal infection, but does influence the development of septic shock. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> Preeclampsia is associated with thrombosis of the intervillous or spiral artery of the placenta. Yamada et al. (2000) <javascript:Anchor('173360_Reference34')> assessed the association between preeclampsia and the 4G/5G polymorphism of the PAI1 gene in 115 preeclampsia patients, 210 pregnant controls, and 298 healthy volunteer controls. The frequency of homozygotes for the 4G allele was significantly higher in the patients than in the control pregnant women or healthy volunteers. The 4G allele frequency was also significantly higher in the patients than in the 2 control groups. 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> The product of the 4G allele of the PAI1 gene binds only an activator, whereas the 5G allele binds an activator and a repressor and is associated with a relatively reduced transcription of PAI1. The 5G variant is associated with less inhibition of the plasminogen activators and, consequently, increased conversion of plasminogen to plasmin and increased activation of matrix metalloproteinases. Thus, patients with this variant may be more at risk of the development of abdominal aortic aneurysm (AAA; 100070). Rossaak et al. (2000) <javascript:Anchor('173360_Reference28')> studied the ratios of the 4G:5G genotypes in 190 patients with AAA, including 39 patients with strong family histories, and 163 controls. The frequency of the 4G:5G alleles in the AAA population and in the control population was 0.6:0.4. However, 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients (P = 0.02) and 0.61 in the control population (P = 0.03). The association of the 5G homozygous genotype with familial AAA questioned the idea that atherosclerosis causes AAAs. Whereas the 4G variant of PAI1 shows a protective role in AAA, it is undesirable in the context of coronary artery disease and atherosclerosis (Harris, 2001 <javascript:Anchor('173360_Reference14')> ). 30 MEDLINE Neighbors<http://www.ncbi.nlm.nih.gov/PMGifs/bright.gif> ________________________________ From: ob-gyn-l@obgyn.net on behalf of Elrod Darryl G MAJ 48 MDOS/SGOBO -- ________________________________ Sent: Thu 4/14/2005 11:10 AM To: Multiple recipients of list OB-GYN-L Subject: Re: Thrombophilias I've never heard of it. I just Googled it and saw it was associated with PAI-1 which I have heard of (vaguely). Glen -----Original Message----- From: ob-gyn-l@obgyn.net [mailto:ob-gyn-l@obgyn.net] On Behalf Of Andrew Folley Sent: Thursday, April 14, 2005 3:59 PM To: Multiple recipients of list OB-GYN-L Subject: Re: Thrombophilias Just when you thought you had the thrombophilia "rat race" figured out they throw in an fresh rat. Anyone have knowledge or experience in dealing with patients with the 5g/5g to 4g/4g gene anomaly????? andy Next message: Stmidwife@aol.com: "Re: VBAC" Previous message: art fougner, md: "Re: VBAC"

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