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Archive for the ‘Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics’ Category

Endocrine Glands: Pathophysiology of Organs

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Chemical Biology and its relations to Metabolic Disease, Population Health Management, Nutrition and Phytochemistry, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , , on June 17, 2013| 2 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

  • Multiple important and complex interactions exist between the endocrine and other systems (e.g. immune, nervous).
  • Definition of hormones: circulating molecules with a site of action distant from site of origin with ability to bind to cellular receptors and initiate signal transduction via conformational changes in the receptor.
  • Hormones participate in growth and development, reproduction, energy metabolism and maintenance of the internal environment.
  • In general, hormones are protein-derived molecules that bind to cell surface receptors or steroid hormones that bind to nuclear receptors. An exemption is thyroid hormone, a modified amino acid that binds to nuclear receptors.
  • Integrated feedback loops are very characteristic to the endocrine system and critical in maintaining normal hormonal function. Two major types of control exist: the hypothalamic-pituitary-peripheral organ unit and the free standing endocrine gland.
  • Pathology in endocrinology is due to abnormal hormone activity or neoplasms, leading to endocrine hyperfunction/hyperfunction or structural abnormalities.

Endocrine pathology is derived from defects found at any point in the hormonal synthesis, secretion, transport, action, or regulatory control of a hormone. Endocrine pathology often occurs in one of the following broad categories:

  1. Abnormal Hormone Activity which can be subdivided into:
    • Endocrine organ hypofunction
      • Primary endocrine organ failure can be genetic or acquired
        • Endocrine organ agenesis (absence)
        • Genetic defect in hormone biosynthetic pathway (e.g. adrenal insufficiency due to 21-hydroxylase deficiency)
        • Destruction due to
          • Autoimmune disease (e.g. Hashimoto’s hypothyroidism)
          • A tumor, infection or hemorrhage
        • Deficiency of precursor (e.g. iodine deficiency leading to decreased thyroid hormone synthesis)
      • Production of abnormal hormone resulting in hypofunction (e.g. abnormal glycosylation of TSH). Secondary endocrine organ failure (e.g. hypothyroidism due to hypopituitarism)
    • Endocrine organ hyperfunction
      • Primary endocrine organ process due to a benign condition (e.g. autoimmune thyroid gland stimulation in Graves’ disease) or benign neoplasm (e.g. primary hyperparathyroidism causing hypercalcemia). Endocrine cancers are rare but they may also release hormones that cause endocrine hyperfunction (e.g. adrenocortical carcinoma secreting excessive androgens causing virilization).
        • Benign condition (e.g. thyroid gland stimulation in Graves’ disease by autoantibodies against the TSH receptor)
        • Benign neoplasm (e.g. primary hyperparathyroid adenoma secreting excessive PTH causing hypercalcemia).
        • Endocrine cancers (e.g. adrenocortical carcinoma secreting excessive androgens causing virilization).
      • Secondary due to stimulation by a trophic/stimulatory hormone, most often due to a benign neoplasm (e.g. hypersecretion of cortisol from adrenal cortex due to and ACTH-secreting pituitary adenoma).
      • Less commonly, ectopic production of a hormone may lead to endocrine hyperfunction (e.g. ACTH released from small cell lung cancer cause hypersecretion of cortisol by adrenal glands).
    • Abnormality in hormone transport or metabolism (e.g. genetic defects of abnormal thyroid binding globulin)
    • Abnormal hormone receptor binding and/or signal transduction. Most often causing endocrine hypofunction due to resistance to the action of hormone. The receptor itself being unable to bind the hormone (e.g. thyroid hormone resistance) or there may be a defect in post-receptor signal transduction (e.g. type 2 diabetes mellitus). Occasionally, abnormal hormone signaling may lead to endocrine hyperfunction (e.g. Gs protein mutation leading to unregulated secretion of Growth Hormone).
  2. Neoplasms. They can be both benign or malignant. Symptoms develop either due to
    • Overproduction of hormone by the tumor (e.g. ACTH producing pituitary adenoma causing hypersecretion of cortisol)
    • Underproduction of nearby hormones due to mass effect (e.g. pituitary hormone production is often affected by large pituitary tumors)
    • Structural damage (e.g. hypothalamic-pituitary tumors causing headache, visual problems).
  3. Iatrogenic. Most common iatrogenic cause of endocrine abnormality is exogenous administration of glucocorticoids (give to treat non-endocrine conditions, e.g. rheumatoid arthritis)

Source References:

http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/

http://ocw.tufts.edu/Content/14/lecturenotes/265876

http://intranet.tdmu.edu.ua/data/kafedra/internal/magistr/classes_stud/English/First%20year/Clinical%20Pathophysiology%20of%20Diseases/CLINICAL%20PATHOPHYSIOLOGY%20OF%20THE%20ENDOCRINE%20SYSTEM.htm

Greenspan FS and Gardner DG. Basic and Clinical Endocrinology, 6th edition. Lange Medical Books, McGraw-Hill, 2001.

Wilson, JD, Foster, DW, Kronenberg, HM, and Larsen, PR. Principles of Endocrinology. In: Williams Textbook of Endocrinology, 9th edition, W.B. Saunders, Philadelphia, 1998.

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Preeclampsia: Pregnency Induced-Hypertension – Potential New Treatment in Development

Posted in HTN, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , , , , , on June 12, 2013| 1 Comment »

Reporter: Aviva Lev-Ari, PhD, RN

PRE-ECLAMPSIA

Preeclampsia is a disorder that occurs only during pregnancy and the postpartum period and affects both the mother and the unborn baby. Affecting at least 5-8% of all pregnancies, it is a rapidly progressive condition characterized by high blood pressure and the presence of protein in the urine. Swelling, sudden weight gain, headaches and changes in vision are important symptoms; however, some women with rapidly advancing disease report few symptoms.

Typically, preeclampsia occurs after 20 weeks gestation (in the late 2nd or 3rd trimesters or middle to late pregnancy) and up to six weeks postpartum, though in rare cases it can occur earlier than 20 weeks. Proper prenatal care is essential to diagnose and manage preeclampsia. Pregnancy Induced Hypertension (PIH) and toxemia are outdated terms for preeclampsia. HELLP syndrome and eclampsia (seizures) are other variants of preeclampsia.

Globally, preeclampsia and other hypertensive disorders of pregnancy are a leading cause of maternal and infant illness and death. By conservative estimates, these disorders are responsible for 76,000 maternal and 500,000 infant deaths each year.

http://www.preeclampsia.org/health-information/about-preeclampsia?gclid=CNeVjpG537cCFUYaOgodC0QASg

VIEW VIDEO – SIX Sections, Pauses in between

http://on.aol.com/video/preeclampsia-vs–pregnancy-induced-hypertension-484063856

  • Preeclampsia vs. Pregnency -Induced Hypertension
  • When Preeclampsia Occur
  • Preeclampsia – Effects on Fetus Health
  • Preeclampsia – Effects on the Baby

Genetic Aspects of Pre-eclampsia

The genetics of pre-eclampsia and other hypertensive disorders of pregnancy

Human Genetics Research Group, School of Molecular and Medical Sciences, University of Nottingham, A Floor West Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK
*Corresponding author. Tel.: +44 (0) 115 8230758; Fax: +44 (0) 115 8230759. Email: Paula.Williams@nottingham.ac.uk
Epidemiological studies clearly confirm a genetic component to pre-eclampsia. Numerous candidate genes have been studied that fall into groups based on their proposed pathological mechanism, including

  • thrombophilia,
  • endothelial function,
  • vasoactive proteins,
  • oxidative stress and
  • lipid metabolism and
  • immunogenetics.
It is expected that no one gene will be identified as the sole risk factor for pre-eclampsia, as in the general population pre-eclampsia represents a complex genetic disorder. Interactions between numerous SNP either alone or with combination with predisposing environmental factors, are most likely underpin the genetic component of this disorder. We must be cautious in our approach to genetics and acknowledge that we are still in the infancy of this research. Following on from GWAS, further fine mapping studies to delineate SNP that are causal from those that are in linkage disequilibrium, followed by functional laboratory studies will be required. Only when we have a better understanding of how the environment interacts with genes will we be in a better position to target treatment for women, for example knowing that women with a certain genotype will benefit from losing weight, enabling us to yield clinical benefit.
At present no genetic test is available to predict pre-eclampsia. The lack of a predictive test can be overcome by careful monitoring and assessment of women, especially those in high-risk groups, including:

    Those at either end of the reproductive age spectrum•Obesity•Black ethnicity•Primiparity•Previous history of pre-eclampsia•Multiple pregnancy•Pre-existing medical conditions: renal disease, insulin-dependent diabetes, autoimmune disease, antiphospholipid syndrom

Genetic aspects of pre-eclampsia

Clustering of cases of pre-eclampsia within families has been recognised since the 19th century, suggesting a genetic component to the disorder.2 Deciphering the genetic involvement in pre-eclampsia is challenging, not least because the phenotype is expressed only in parous women. Furthermore, in complex disorders of pregnancy, it is necessary to consider two genotypes, that of the mother and that of the fetus, which includes genes inherited from both mother and father. Maternal and fetal genes may have independent or interactive effects on the risk of pre-eclampsia. Finally, the heterogeneous nature of the disorder, with a sliding scale of severity, has resulted in differences in the definition of pre-eclampsia used within studies (see above), often with overlap of non-proteinuric gestational hypertension.

Twin studies investigating the relative contribution of genetic versus environmental factors to pre-eclampsia risk, initially yielded disappointing results. They showed that discordance for pre-eclampsia between monozygotic twin sisters was common, suggesting that heritability caused by maternal genes was low.3 These early studies were small. More recent investigations, however, using the large Swedish Twin, Medical Birth and Multigeneration Registries have estimated the heritability of pre-eclampsia to be about 55%, with contributions from both maternal and fetal genes. A further study in monozygotic twins4 found concordance of pre-eclampsia to be as common as discordance. Evidence from the largest published twin study, which correlated the Swedish Twin Register with the Swedish Medical Register, revealed pre-eclampsia penetrance to be less than 50%, suggesting diversity within models of inheritance.5–7

Pre-eclampsia: a complex genetic disorder

For a small number of families, pre-eclampsia seems to follow Mendelian patterns of disease inheritance,8 consistent with a rare deleterious monogenic variant or mutation with high penetrance. For most of the population, however, pre-eclampsia seems to represent a complex genetic disorder, and occurs as the result of numerous common variants at different loci which, individually, have small effects but collectively contribute to an individual’s susceptibility to disease. Environmental exposures, including age and weight, also determine whether these low penetrant variants result in phenotypic manifestation of the disease. It is likely that no single cause or genetic variant will account for all cases of pre-eclampsia, although it is possible that different variants are associated with various subsets of disease (e.g. pre-eclampsia combined with intrauterine growth restriction). Complex genetic disorders affect a high proportion of the population, representing a large burden to public health. New approaches to susceptibility gene discovery have emerged to address this challenge. Unfortunately, early diagnosis would only permit closer focus on routine antenatal care, as at present no intervention other than delivery has been shown to alter the course of pre-eclampsia.

Determining susceptibility to pre-eclampsia

The need to assess both the maternal and the fetal genotype is clear. The role of the placenta in the primary pathogenesis of the disorder indisputably indicates a fetal contribution to susceptibility to the disorder.9 Reports of severe, very early-onset pre-eclampsia in cases of fetal chromosomal abnormalities such as diandric hydatifidiform moles of entirely paternal genetic origin10 are consistent with a role for paternally inherited fetal genes in the determination of clinical phenotype. This is supported by epidemiological studies reporting a higher rate of pre-eclampsia in pregnancies fathered by men who were themselves born of pre-eclamptic pregnancies.11 The occurrence of pre-eclampsia in daughters-in-law of index women9 further supports a genetic contribution from both parents. The genetic conflict hypothesis states that fetal (paternal) genes will be selected to increase the transfer of nutrients to the fetus, whereas maternal genes will be selected to limit transfer in excess of a specific maternal optimum.12 Fetal genes are predicted to raise maternal blood pressure in order to enhance the uteroplacental blood flow, whereas maternal genes act the opposite way. Endothelial dysfunction in mothers with pre-eclampsia could, therefore, be interpreted as a fetal attempt to compensate for an inadequate uteroplacental nutrient supply.

As the phenotype is apparently only expressed during pregnancy, identification of ‘susceptible’ men is impossible. Most genetic studies of pre-eclampsia have focused on maternal genotypes only. The Genetics of Pre-eclampsia consortium highlighted the need to include analysis of all contributing genotypes, and carried out transmission disequilibrium testing in maternal and fetal triads.13 Understanding the contribution of the fetal genotype will require large sample sizes, with the development of algorithms to determine the relative contribution from mother and fetus. Furthermore, the decreased incidence of pre-eclampsia in second and subsequent pregnancies hampers analysis of the contribution of the fetal genotype.

Candidate gene approach

The candidate gene approach has been widely used in pre-eclampsia, and largely focuses on the maternal genotype. In this method, a single gene is chosen as the candidate for investigation based on prior biological knowledge of the pathophysiology of pre-eclampsia. The choice is strengthened if the gene lies within a region identified by linkage studies. A case-control design is usually used, comparing the frequencies of allelic variants in women with pre-eclampsia and normotensive pregnancies. Such studies need careful definition of inclusion criteria for cases and controls, and subtle ethnic stratification of groups must be avoided. Such performance characteristics of the genotyping assays as the rate of mis-genotyping, and the quality assurance methods used, should be clearly stated, but this is rarely done. Over 70 biological candidate genes have been examined, representing pathways involved in various pathophysiological processes, including vasoactive proteins, thrombophilia and hypofibrinolysis, oxidative stress and lipid metabolism, endothelial injury and immunogenetics.14 In common with the experience in other genetically complex disorders, results from candidate gene studies have been inconsistent, and no universally accepted susceptibility gene has been identified. Although this may, in part, be attributed to variation within populations, a more important factor is the small size of most of the candidate studies, which have been underpowered to detect variants with small effects. As there are more than 20,000 genes and 10 million single nucleotide polymorphisms (SNP) available, multiple testing will inevitably result in numerous results that achieve P values of less than 0.05. The development of robust statistical techniques for the minimisation of both false positive and false negative results is an important area.15,16 Only in recent years, as susceptibility genes for other complex disorders have been reported, has the small effect size of individual genetic variants become apparent, the majority increasing the risk of disease by less than 50%. A further limitation of the candidate gene approach is its reliance on the generation of an a-priori hypothesis based on our current incomplete knowledge of the pathophysiology of the disorder. The candidate genes studied belong to different groups according to their functional properties and plausible role in the pathophysiology (Table 2).

Thrombophilia

A successful pregnancy requires the development of adequate placental circulation. It is hypothesised that thrombophilias may increase the risk of placental insufficiency because of placental micro-vascular thrombosis, macro-vascular thrombosis, or both, as well as effects on trophoblast growth and differentiation.17 Abnormalities of the clotting cascade are well documented in women with pre-eclampsia.18 The endothelial damage of pre-eclampsia is associated with an altered phenotype from anticoagulant to procoagulant and decreased endothelially mediated vasorelaxation. It is possible that this phenotype is present before pre-eclampsia in pregnancy, or it may develop as a consequence of damage initiated during placentation. Furthermore, a subset of women develop frank thrombocytopaenia, often in association with haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Association of the three most widely studied thrombophilic factors, factor V Leiden (F5), methylenetetrahydrofolate (MTHFR) and prothrombin (F2), with pre-eclampsia has been shown; however, several studies have also shown contradictory results.14 A recent meta-analysis indicated a two-fold increase in risk for pre-eclampsia associated with 1691G>A mutation in F5, but no associations were found for MTHFR or F2.19 To date, the number of studies showing no association with pre-eclampsia for these three genes is much higher than the number confirming association. Association with the inhibitor of fibrinolysis plasminogen activator factor-1 gene has also been reported; however, replication attempts have failed.20–22

Haemodynamics and endothelial function

The renin-angiotensin system (RAS) is important for regulating the cardiovascular and renal changes that occur in pregnancy. Several studies have implicated the RAS in the pathophysiology of pre-eclampsia.23 As such, genes in the RAS have been considered as plausible candidates for pre-eclampsia. Angiotensin-converting enzyme (ACE), angiotensin II type 1 and type 2 receptor (AGTR1, AGTR2), and angiotensinogen (AGT) have all been studied extensively in pre-eclampsia. Recent meta-analyses have identified the T allele of AGT M235T as increasing the risk of developing pre-eclampsia by 1.62 times and similar increases in disease risk have been found in AGT and the angiotensin-converting enzyme I/D polymorphism.24 A rare functional polymorphism in AGT, which results in replacement of leucine by phenylalanine at the site of renin cleavage, has been reported in association with severe pre-eclampsia.25

Endothelial nitric oxide synthase 3 (eNOS3), which is involved in vascular remodelling and vasodilation, has been shown to have reduced activity in pre-eclampsia26 Association studies in different ethnic populations, however, have yielded both positive and negative findings. A meta-analysis investigating the E298D polymorphism, which had initially been associated with pre-eclampsia in Colombian women, failed to find increased risk.24 Vascular endothelial growth factor (VEGF) is important for endothelial cell proliferation, migration, survival and regulation of vascular permeability. The number of studies that have investigated SNP in the genes involved in the VEGF system is small. Two polymorphisms in VEGF, 405G>C and 936C>T, were found to be associated with the severe form of pre-eclampsia in two small studies, but cannot at present be considered as major risk factors.27,28

Oxidative stress and lipid metabolism

Oxidative stress plays a central role in the pathogenesis of pre-eclampsia. Maternal perfusion of the placenta does not occur until towards the end of the first trimester,29 when a rapid increase in local oxygen tension takes place, and the probable occurrence of a period of hypoxia–reperfusion until stability is reached. This is accompanied by increased expression and activity of such antioxidants as glutathione peroxidase, catalase and the various forms of superoxide dismutase.30 If this antioxidant response were reduced, then the cascade of events leading to impaired placentation could be initiated. Evidence for reduced antioxidant activity in pre-eclampsia has recently been reviewed.31 Genes involved in the generation or inactivation of reactive oxygen species, if defective, could increase endothelial dysfunction via lipid peroxidation, which has been a candidate causative agent for the endothelial damage of pre-eclampsia for more than 20 years.32 Despite the strong correlation between oxidative stress and pre-eclampsia, only a small handful of genes have been investigated. Functional polymorphisms in the gene for microsomal epoxide hydrolase (EPHX) that catalyses the hydrolysis of certain oxides and may produce toxic intermediates that could be involved in pre-eclampsia, and glutathione S-transferase (GST), an antioxidant capable of inactivating reactive oxygen species, have shown associations. Conflicting results, however, have also been reported.33–36

Abnormal lipid profiles associated with the lipid peroxidation caused by oxidative stress are also characteristic of pre-eclampsia. Lipoprotein lipase (LPL) and apolipoprotein E (ApoE) are the two major regulators of lipid metabolism, abundantly expressed in placenta, and have therefore been proposed as possible candidate genes.37,38 A recent study using bioinformatic analysis identified altered glycosylation of circulating ApoE isoforms in pre-eclampsia.39 A deglycosylated basic ApoE isoform was increased in pre-eclampsia, and an acidic ApoE sialyated isoform was decreased. Functionally, this might increase the risk of developing placental atherotic changes. The most promising genetic variant in this context is a mis-sense mutation, Asn291Ser, in LPL which correlates with lowered LPL activity and increased dyslipidaemia in two separate studies. Again, others have failed to replicate these findings.38,40,41 The fetal genotype of these two genes has also been reported to contribute to the metabolism of the maternal lipoproteins.37

Immune system

The maternal immune response to pregnancy is crucial in determining pregnancy outcome and success. The increased incidence of pre-eclampsia in primiparous women, especially those at either end of the childbearing age range, indicates a strong association between immune factors and pre-eclampsia.42 However, the protective effect of multiparity is lost with change of partner. Advances in assisted reproductive technology are also posing new challenges to the maternal immune system. The use of donated sperm or eggs increases the risk of pre-eclampsia three-fold.43

Human leucocyte antigen

Trophoblast cells express an unusual repertoire of histocompatibility antigens, comprising human leucocyte C, E and G class antigens (HLA-C, HLA-E, HLA-E), of which only HLA-C displays marked polymorphism. The expression of HLA on the invading cytotrophoblast is important, as these interact with killer immunoglobulin, such as receptors (KIR) expressed on maternal uNKs and cytotoxic T-lymphocytes, down-regulating their cytolytic activity and stimulating the production of cytokines needed for successful placentation. Multiple highly homologous KIR genes map to chromosome 19q, probably arising from ancestral gene duplications, and the two main resulting gene clusters have been classified as haplotypes A and B. The A group codes mainly for KIR, which inhibit natural killer cells, whereas the B group has additional stimulatory genes.44 Pre-eclampsia is more frequent in women who are homozygous for the inhibitory A haplotypes (AA) than in women homozygous for the stimulatory B haplotypes (BB). The effect is strongest if the fetus is homozygous for the HLA-C2 haplotype.45 Alteration in KIR interaction on uNK cells with HLA-C on interstitial trophoblast alters the decidual immune response, resulting in impaired extravillous trophoblast invasion and deficient spiral artery remodelling, associated with pre-eclampsia.

An association of HLA-G, which displays limited polymorphism, with pre-eclampsia, has also been reported. A possible association between the presence of the HLA-G allele G*0106 in the placenta and an increased risk of pre-eclampsia has been identified in two small studies.46,47 these were underpowered, however, and further studies using larger cohorts of mothers and babies are needed to replicate these results. HLA-G variants foreign to the mother may lead to histo-incompatibility between mother and child. A maternal rejection response to the semi-allogeneic fetus may represent one of the pathways involved in the development of pre-eclampsia.

A number of pro-inflammatory cytokines have also been investigated for possible associations with pre-eclampsia. Excessive release of tumour necrosis factor alpha (TNFα) has been implicated owing to its contribution to endothelial activation, which in turn could contribute to maternal symptoms.48 Interestingly, in pregnant rats, TNF induces hypertension, a response not seen in non-pregnant rats.49 Furthermore, plasma levels of TNFα are significantly higher in women with pre-eclampsia than matched controls.50 TNFα is also involved in the production of reactive oxygen species and subsequently oxidant mediated endothelial damage. The most frequently studied variant in pre-eclampsia is the –308G>A transition in the promoter region, which is associated with increased levels of TNFα production and an increased risk for pre-eclampsia linked disorders, including type 2 diabetes, coronary artery disease and dyslipidaemia.51,52 However, a meta-analysis from 2008 combined 16 studies investigating this promoter SNP, but failed to detect a significant association to pre-eclampsia.53

Interleukin-10 (IL-10) has also been implicated in the pathogenesis of pre-eclampsia by enhancing the inflammatory response towards trophoblast cells resulting in reduced invasion and remodelling of the spiral arteries.54 Expression of IL-10 is reduced in pre-eclamptic placentae.55 Studies investigating associations of variants of the gene and pre-eclampsia, however, have yielded conflicting results.56–58 Associations have also been detected for two additional inflammatory genes, interleukin-1α (IL-1α) and the interleukin 1 receptor anatagonist (IL1Ra) in relatively small studies, but few studies have addressed the role of polymorphisms in these genes so far.59,60

Antioxidant enzymes

A large family of cytosolic glutathione-s-transferases (GST) exists, and the P class is highly expressed in the human placenta. Several relatively small case-control studies of polymorphisms in this family in relation to pre-eclampsia have failed to identify any significant effect of several GST polymorphisms studied individually. However, a cumulative effect of the number of polymorphisms in various biotransformation enzymes, including GST, which would result in decreased antioxidant capacity, has been reported.61 Intriguingly, the use of semi-quantitative polymerase chain reaction on a small data set identified using serial analysis of gene expression profiles, seems to identify a specific molecular signature for HELLP, which includes decreased expression of GST P1.62

Remarkably, few studies of possible functional polymorphisms in antioxidant enzyme systems have been reported. The 242C>T polymorphism in exon 4 of the gene for the p22phox subunit of NADPH/NADH oxidase (CYBA), which is part of the cascade of superoxide generation, has been reported as showing no evidence of an association with either pre-eclampsia or HELLP and pre-eclampsa.63 A small preliminary study of the Ala40Thr polymorphism of the superoxide dismutase 3 gene (SOD3), which has been associated with insulin resistance, reported a significant excess of the mutant allele in women with severe intrauterine growth restriction.64

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145161/?report=printable

High blood pressure in pregnancy: What’s your story?

By Mary M. Murry, R.N., C.N.M.

Blood pressure tends to fluctuate during pregnancy.

For example, it’s normal to experience a drop in blood pressure during the second trimester. In fact, your blood pressure might be lower than it’s ever been. During the third trimester, a gradual increase in blood pressure is common.

Sometimes, though, blood pressure changes more dramatically — or sustained high blood pressure becomes a concern.

By definition, there are various types of high blood pressure during pregnancy:

  • Chronic hypertension. If high blood pressure develops before pregnancy or during pregnancy but before 20 weeks, it’s known as chronic hypertension. High blood pressure that lasts more than 12 weeks after delivery is also considered chronic hypertension.
  • Gestational hypertension. If high blood pressure develops after 20 weeks of pregnancy, it’s known as gestational hypertension. Gestational hypertension usually goes away after delivery.
  • Preeclampsia. Sometimes chronic hypertension or gestational hypertension leads to preeclampsia. This is a serious condition characterized by high blood pressure and protein in the urine after 20 weeks of pregnancy.

All of these conditions can be dangerous for you and your baby. If your pregnancy has been normal until now, a diagnosis of high blood pressure can be especially jarring.

Depending on the circumstances, your health care provider might recommend close monitoring or, in some cases, an early delivery.

Count on your health care provider to help you understand what’s happening and what you can do to promote a healthy outcome. Above all, don’t hesitate to ask questions. Being fully informed can help you make the best decisions for you and your baby.

http://www.mayoclinic.com/health/high-blood-pressure-in-pregnancy/MY02263

Texas A&M Researcher Uncovers New Data for the Treatment of Preeclampsia

Posted Thursday , June 06,2013

preeclampsia

A Researcher From Texas A&M Has Uncovered New Data for the Treatment of Preeclampsia: Preclinical Research Shows PLX Cells May Be Effective in Treating Preeclampsia.

Preliminary research led by Brett Mitchell, PhD, an Associate Professor of Internal Medicine in the Cardiovascular Research Institute (CVRI) at Texas A&M University College of Medicine, is demonstrating that administrating placental stem cells may aid in reversing symptoms linked with preeclampsia within days after dosing with no apparent harmful effects to fetus or mother.

Preeclampsia may occur after the 20th week of pregnancy when the mother-to-be’s blood pressure has increased and there are signs of excessive protein in the urine. This condition affects somewhere between 6-8 percentage of pregnancies in the US, and can be serious, as there is a shift from protecting mother and fetus as immunologically privileged sites. This brings about vascular issues that involve the inability of blood vessels to dilate or relax.

Dr. Mitchel has been able to look at the immune cells that are responsible for the development of high blood pressure (hypertension) during pregnancy in hopes to develop new therapies that diminish the immune cells that are responsible for this action while maintaining normal immune cell function.

Mitchel and colleagues have taken mice that had preeclampsia and injected placenta-based cells (stem cells) known as PLX (Placentall eXpanded) into leg muscle.  PLX cells are used as a way of delivering drugs and in particular therapeutic proteins in response to inflammatory and ischemic events.  They tested eight groups of 2 separate animal models (preeclampsia models) and found that PLX cells were effective in treating preeclampsia.

They observed a reduction in

  • systolic pressure to normal levels within 3 days and a reduction of
  • urinary proteins within 4 days.

They also observed an

  • increase in endothelial function.  This was measured by acetylcholine-induced relaxation and was effective within 4 days. A
  • weight reduction of the spleen was also observed within 4 days.

Pregnant mice who didn’t have preeclampsia were subjected to the same protocol and it was found that muscle injection of PLX cells did not effect a normal pregnancy.  They also found that the number of pups or fetal demise in a litter were not different indicating that PLX cells caused no fetal harm.

Dr. Mitchel presented his findings at the Society for Gynecologic Investigation Summit in Jerusalem on May 30, 2013.  Mitchell suggests that the factors that were secreted from the PLX cells were able to decrease inflammation thereby restoring endothelial function.

Currently, there are no treatments available for preeclampsia, so this therapy looks promising.

http://bionews-tx.com/news/2013/06/06/texas-a-and-m-new-data-for-the-treatment-of-preeclampsia-preclinical-research-shows-plx-cells-may-be-effective-in-treating-preeclampsia/

REFERENCE

http://www.preeclampsia.org/health-information/about-preeclampsia?gclid=CNeVjpG537cCFUYaOgodC0QASg

  1. Pregnancy. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/hbp/issues/preg/preg.htm. Accessed March 9, 2011.
  2. Conde-Agudelo A, et al. Maternal infection and risk of preeclampsia: Systematic review and metaanalysis. American Journal of Obstetrics and Gynecology. 2008;198:7.
  3. Bodnar LM, et al. Maternal vitamin D deficiency increases the risk of preeclampsia. Journal of Clinical Endocrinology & Metabolism. 2007;92:3517.
  4. High blood pressure and preeclampsia. March of Dimes. http://www.marchofdimes.com/complications_preeclampsia.html. Accessed March 9, 2011.
  5. Norwitz ER, et al. Management of preeclampsia. http://www.uptodate.com/home/index.html. Accessed March 7, 2011.
  6. Leanos-Miranda A, et al. Urinary prolactin as a reliable marker for preeclampsia, its severity, and the occurrence of adverse pregnancy outcomes. Journal of Clinical Endocrinology & Metabolism. 2008;93:2492.
  7. August P, et al. Clinical features, diagnosis, and long-term prognosis of preeclampsia. http://www.uptodate.com/home/index.html. Accessed March 7, 2011.
  8. Sibai BM, et al. Hypertension. In: Gabbe SG, et al. Obstetrics: Normal and Problem Pregnancies. 5th ed. Philadelphia, Pa.: Churchill Livingstone Elsevier; 2007. http://www.mdconsult.com/das/book/body/208746819-4/0/1528/0.html. Accessed March 9, 2011.
  9. Barton JR, et al. Prediction and prevention of recurrent preeclampsia. Obstetrics & Gynecology. 2008;112:359.
  10. Bellamy L, et al. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: Systematic review and meta-analysis. British Medical Journal. 2007;335:974.
  11. Facchinetti F, et al. Migraine is a risk factor for hypertensive disorders in pregnancy: A prospective cohort study. Cephalalgia: An International Journal of Headache. 2009;29:286.
  12. Steegers EA, et al. Pre-eclampsia. The Lancet. 2010;376:631.

REFERENCES ON THE GENETICS of PRE-ECLAMPSIA in

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145161/?report=printable

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145161/?report=printable

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Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies

Posted in Alzheimer's Disease, Biological Networks, Gene Regulation and Evolution, Cardiovascular Pharmacogenomics, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Etiology, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , , , , , , , , , , , , , , , , on May 15, 2013| 5 Comments »

Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

Writer and Reporter: Stephen J. Williams, Ph.D.

Article 2.7 Finding the Genetic Links in Common Disease:  Caveats of Whole Genome Sequencing Studies

In the November 23, 2012 issue of Science, Jocelyn Kaiser reports (Genetic Influences On Disease Remain Hidden in News and Analysis)[1] on the difficulties that many genomic studies are encountering correlating genetic variants to high risk of type 2 diabetes and heart disease.  At the recent American Society of Human Genetics annual 2012 meeting, results of several DNA sequencing studies reported difficulties in finding genetic variants and links to high risk type 2 diabetes and heart disease.  These studies were a part of an international effort to determine the multiple genetic events contributing to complex, common diseases like diabetes.  Unlike Mendelian inherited diseases (like ataxia telangiectasia) which are characterized by defects mainly in one gene, finding genetic links to more complex diseases may pose a problem as outlined in the article:

  • Variants may be so rare that massive number of patient’s genome would need to be analyzed
  • For most diseases, individual SNPs (single nucleotide polymorphisms) raise risk modestly
  • Hard to find isolated families (hemophilia) or isolated populations (Ashkenazi Jew)
  • Disease-influencing genes have not been weeded out by natural selection after human population explosion (~5000 years ago) resulted in numerous gene variants
  • What percentage variants account for disease heritability (studies have shown this is as low as 26% for diabetes with the remaining risk determined by environment)

Although many genome-wide-associations studies have found SNPs that have causality to increasing risk diseases such as cancer, diabetes, and heart disease, most individual SNPs for common diseases raise risk by about only 20-40% and would be useless for predicting an individual’s chance they will develop disease and be a candidate for a personalized therapy approach.  Therefore, for common diseases, investigators are relying on direct exome sequencing and whole-genome sequencing to detect these medium-rare risk variants, rather than relying on genome-wide association studies (which are usually fine for detecting the higher frequency variants associated with common diseases).

Three of the many projects (one for heart risk and two for diabetes risk) are highlighted in the article:

1.  National Heart, Lung and Blood Institute Exome Sequencing Project (ESP)[2]: heart, lung, blood

  • Sequenced 6,700 exomes of European or African descent
  • Majority of variants linked to disease too rare (as low as one variant)
  • Groups of variants in the same gene confirmed link between APOC3 and higher risk for early-onset heart attack
  • No other significant gene variants linked with heart disease

2.  T2D-GENES Consortium: diabetes

Sequenced 5,300 exomes of type 2 diabetes patients and controls from five ancestry groups
SNP in PAX4 gene associated with disease in East Asians
No low-frequency variant with large effect though

3.  GoT2D: diabetes

  • After sequencing 2700 patient’s exomes and whole genome no new rare variants above 1.5% frequency with a strong effect on diabetes risk

A nice article by Dr. Sowmiya Moorthie entitled Involvement of rare variants in common disease can be found at the PGH Foundation site http://www.phgfoundation.org/news/5164/ further discusses this conundrum,  and is summarized below:

“Although GWAs have identified many SNPs associated with common disease, they have as yet had little success in identifying the causative genetic variants. Those that have been identified have only a weak effect on disease risk, and therefore only explain a small proportion of the heritable, genetic component of susceptibility to that disease. This has led to the common disease-common variant hypothesis, which predicts that common disease-causing genetic variants exist in all human populations, but each individual variant will necessarily only have a small effect on disease susceptibility (i.e. a low associated relative risk).

An alternative hypothesis is the common disease, many rare variants hypothesis, which postulates that disease is caused by multiple strong-effect variants, each of which is only found in a few individuals. Dickson et al. in a paper in PLoS Biology postulate that these rare variants can be indirectly associated with common variants; they call these synthetic associations and demonstrate how further investigation could help explain findings from GWA studies [Dickson et al. (2010) PLoS Biol. 8(1):e1000294][3].  In simulation experiments, 30% of synthetic associations were caused by the presence of rare causative variants and furthermore, the strength of the association with common variants also increased if the number of rare causative variants increased. “

one_of_many rare variants

Figure from Dr. Moorthie’s article showing the problem of “finding one in many”.

(please   click to enlarge)

Indeed, other examples of such issues concerning gene variant association studies occur with other common diseases such as neurologic diseases and obesity, where it has been difficult to clearly and definitively associate any variant with prediction of risk.

For example, Nuytemans et. al.[4] used exome sequencing to find variants in the vascular protein sorting 3J (VPS35) and eukaryotic transcription initiation factor 4  gamma1 (EIF4G1) genes, tow genes causally linked to Parkinson’s Disease (PD).  Although they identified novel VPS35 variants none of these variants could be correlated to higher risk of PD.   One EIF4G1 variant seemed to be a strong Parkinson’s Disease risk factor however there was “no evidence for an overall contribution of genetic variability in VPS35 or EIF4G1 to PD development”.

These negative results may have relevance as companies such as 23andme (www.23andme.com) claim to be able to test for Parkinson’s predisposition.  To see a description of the LLRK2 mutational analysis which they use to determine risk for the disease please see the following link: https://www.23andme.com/health/Parkinsons-Disease/. This company and other like it have been subjects of posts on this site (Personalized Medicine: Clinical Aspiration of Microarrays)

However there seems to be more luck with strategies focused on analyzing intronic sequence rather than exome sequence. Jocelyn Kaiser’s Science article notes this in a brief interview with Harry Dietz of Johns Hopkins University where he suspects that “much of the missing heritability lies in gene-gene interactions”.  Oliver Harismendy and Kelly Frazer and colleagues’ recent publication in Genome Biology  http://genomebiology.com/content/11/11/R118 support this notion[5].  The authors used targeted resequencing of two endocannabinoid metabolic enzyme genes (fatty-acid-amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal weight and 142 extremely obese patients.

These patients were enrolled in the CRESCENDO trial and patients analyzed were of European descent. However, instead of just exome sequencing, the group resequenced exome AND intronic sequence, especially focusing on promoter regions.   They identified 1,448 single nucleotide variants but using a statistical filter (called RareCover which is referred to as a collapsing method) they found 4 variants in the promoters and intronic areas of the FAAH and MGLL genes which correlated to body mass index.  It should be noted that anandamide, a substrate for FAAH, is elevated in obese patients. The authors did note some issues though mentioning that “some other loci, more weakly or inconsistently associated in the original GWASs, were not replicated in our samples, which is not too surprising given the sample size of our cohort is inadequate to replicate modest associations”.

PLEASE WATCH VIDEO on the National Heart, Lung and Blood Institute Exome Sequencing Project

https://www.youtube.com/watch?v=-Qr5ahk1HEI

REFERENCES

http://www.phgfoundation.org/news/5164/  PHG Foundation

1.            Kaiser J: Human genetics. Genetic influences on disease remain hidden. Science 2012, 338(6110):1016-1017.

2.            Tennessen JA, Bigham AW, O’Connor TD, Fu W, Kenny EE, Gravel S, McGee S, Do R, Liu X, Jun G et al: Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012, 337(6090):64-69.

3.            Dickson SP, Wang K, Krantz I, Hakonarson H, Goldstein DB: Rare variants create synthetic genome-wide associations. PLoS biology 2010, 8(1):e1000294.

4.            Nuytemans K, Bademci G, Inchausti V, Dressen A, Kinnamon DD, Mehta A, Wang L, Zuchner S, Beecham GW, Martin ER et al: Whole exome sequencing of rare variants in EIF4G1 and VPS35 in Parkinson disease. Neurology 2013, 80(11):982-989.

5.            Harismendy O, Bansal V, Bhatia G, Nakano M, Scott M, Wang X, Dib C, Turlotte E, Sipe JC, Murray SS et al: Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level. Genome biology 2010, 11(11):R118.

Other posts on this site related to Genomics include:

Cancer Biology and Genomics for Disease Diagnosis

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

Genomics-based cure for diabetes on-the-way

Personalized Medicine: Clinical Aspiration of Microarrays

Late Onset of Alzheimer’s Disease and One-carbon Metabolism

Genetics of Disease: More Complex is How to Creating New Drugs

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New CEGS on the Brain: Mental Disorders and the Nervous System

Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed

Mitochondrial Metabolism and Cardiac Function

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Quantum Biology And Computational Medicine

Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Centers of Excellence in Genomic Sciences (CEGS): NHGRI to Fund New CEGS on the Brain: Mental Disorders and the Nervous System

LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Consumer Market for Personal DNA Sequencing: Part 4

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3

Whole-Genome Sequencing Data will be Stored in Coriell’s Spin off For-Profit Entity

 

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Reproductive Genetic Testing

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , , , , , , , , , , , , on March 18, 2013| 2 Comments »

Reproductive Genetic Testing

Reporter and Curator: Sudipta Saha, Ph.D.

Reproductive genetics, a field of medical genetics integrated with reproductive medicine, assisted reproduction, and developmental genetics, involves a wide array of genetic tests that are conducted with the intent of informing individuals about the possible outcomes of current or future pregnancies. The tests themselves can include the analysis of chromosomes, DNA, RNA, genes, and/or gene products to determine whether an alteration is present that is causing or is likely to cause a specific disease or condition.

Types of Tests

In general, reproductive genetic testing involves the following categories of tests:

Carrier testing is performed to determine whether an individual carries one copy of an altered gene for a particular recessive disease. The term recessive refers to diseases that will occur only if both copies of a gene that an individual receives have a disease-associated mutation; thus, each child born to two carriers of a mutation in the same gene has a 25 percent risk of being affected with the disorder. Examples of carrier tests include those for

Couples are likely to have carrier tests if they are at higher risk of having a child with a specific disorder because of their racial or ethnic heritage or family history. Carrier testing is often done in the context of family planning and reproductive health.

Preimplantation diagnosis is used following in vitro fertilization to diagnose a genetic disease or condition in a preimplantation embryo. Preimplantation genetic diagnosis is essentially an alternative to prenatal diagnosis, as it allows prenatal testing to occur months earlier than conventional tests such as amniocentesis on week 18th of pregnancy, even before a pregnancy begins. Doctors can test a single cell from an eight-cell embryo that is just days old to determine, among other things, whether it is a male or female. This can provide crucial information for genetic diseases that afflict just one sex. Preimplantation genetic diagnosis has been applied to patients carrying chromosomal rearrangements, such as translocations, in which it has been proven to decrease the number of spontaneous abortions and prevent the birth of children affected with chromosome imbalances. Preimplantation genetic diagnosis techniques have also been applied to

  • increase implantation rates,
  • reduce the incidence of spontaneous abortion, and
  • prevent trisomic offspring in women of advanced maternal age undergoing fertility treatment.

A third group of patients receiving preimplantation genetic diagnosis are those at risk of transmitting a single gene disorder to their offspring. The number of monogenic disorders that have been diagnosed in preimplantation embryos has increased each year. So far, at least 700 healthy babies have been born worldwide after undergoing the procedure, and the number is growing rapidly.

Prenatal diagnosis is used to diagnose a genetic disease or condition in a developing fetus.

The techniques currently in use or under investigation for prenatal diagnosis include

  • (1) fetal tissue sampling through amniocentesis, chorionic villi sampling (CVS), percutaneous umbilical blood sampling, percutaneous skin biopsy, and other organ biopsies, including muscle and liver biopsy;
  • (2) fetal visualization through ultrasound, fetal echocardiography, embryoscopy, fetoscopy, magnetic resonance imaging, and radiography;
  • (3) screening for neural tube defects by measuring maternal serum alpha-fetoprotein (MSAFP);
  • (4) screening for fetal Down Syndrome by measuring MSAFP, unconjugated estriol, and human chorionic gonadotropin;
  • (5) separation of fetal cells from the mother’s blood; and
  • (6) preimplantation biopsy of blastocysts obtained by in vitro fertilization.

The more common techniques are amniocentesis, performed at the 14th to 20th week of gestation, and CVS, performed between the 9th and 13th week of gestation. If the fetus is found to be affected with a disorder, the couple can plan for the birth of an affected child or opt for elective abortion.

Newborn screening is performed in newborns on a public health basis by the states to detect certain genetic diseases for which early diagnosis and treatment are available. Newborn screening is one of the largest public health activities in the United States. It is aimed at the early identification of infants who are affected by certain genetic, metabolic or infectious conditions, reaching approximately 4 million children born each year. According to the Centers for Disease Control and Prevention (CDC), approximately 3,000 babies each year in the United States are found to have severe disorders detected through screening. States test blood spots collected from newborns for 2 to over 30 metabolic and genetic diseases, such as

  • phenylketonuria,
  • hypothyroidism,
  • galactosemia,
  • sickle cell disease, and
  • medium chain acyl CoA dehyrogenase deficiency.

The goal of this screening is to identify affected newborns quickly in order to provide treatment that can prevent mental retardation, severe illness or death.

It is possible that somatic cell nuclear transfer (cloning) techniques could eventually be employed for the purposes of reproductive genetic testing. In addition, germline gene transfer is a technique that could be used to test and then alter the genetic makeup of the embryo. To date, however, these techniques have not been used in human studies.

Ethical Issues

Any procedure that provides information that could lead to a decision to terminate a pregnancy is not without controversy. Although prenatal diagnosis has been routine for nearly 20 years, some ethicists remain concerned that the ability to eliminate potential offspring with genetic defects contributes to making society overall less tolerant of disability. Others have argued that prenatal diagnosis is sometimes driven by economic concerns because as a society we have chosen not to provide affordable and accessible health care to everyone. Thus, prenatal diagnosis can save money by preventing the birth of defective and costly children. For reproductive genetic procedures that involve greater risk to the fetus, e.g., preimplantation diagnosis, concerns remain about whether the diseases being averted warrant the risks involved in the procedures themselves. These concerns are likely to escalate should

  • cloning or
  • germline gene transfer

be undertaken as a way to genetically test and select healthy offspring.

SOURCE:

http://www.genome.gov/10004766

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Sexed Semen and Embryo Selection in Human Reproduction and Fertility Treatment

Posted in Biological Networks, Gene Regulation and Evolution, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , , , , , , , , , on March 11, 2013| 2 Comments »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Use of sexed semen in conjunction with in vitro embryo production is a potentially efficient means of obtaining offspring of predetermined sex. Sperm sorting is a means of choosing what type of sperm cell is to fertilize the egg cell. It can be used to sort out sperm that are most healthy, as well as determination of more specific traits, such as sex selection in which spermatozoa are separated into X- (female) and Y- (male) chromosome bearing populations based on their difference in DNA content. The resultant ‘sex-sorted’ spermatozoa are then able to be used in conjunction with other assisted reproductive technologies such as artificial insemination or in-vitro fertilization (IVF) to produce offspring of the desired sex. DNA damage in sperm cells may be detected by using Raman spectroscopy.  It is not specific enough to detect individual traits, however. The sperm cells having least DNA damage may subsequently be injected into the egg cell by intracytoplasmic sperm injection (ICSI).

Sperm sorting utilizes the technique of flow cytometry to analyze and ‘sort’ spermatozoa. During the early to mid 1980s, Dr. Glenn Spaulding was the first to sort viable whole human and animal spermatozoa using a flow cytometer, and utilized the sorted motile rabbit sperm for artificial insemination. Subsequently, the first patent application disclosing the method to sort “two viable subpopulations enriched for x- or y- sperm” was filed in April 1987 and the patent included the discovery of haploid expression (sex-associated membrane proteins, or SAM proteins) and the development of monoclonal antibodies to those proteins. Additional applications and methods were added, including antibodies, from 1987 through 1997. At the time of the patent filing, both Lawrence Livermore National Laboratories and the USDA were only sorting fixed sperm nuclei, after the patent filing a new technique was utilized by the USDA where “sperm were briefly sonicated to remove tails”. USDA in conjunction with Lawrence Livermore National Laboratories, ‘Beltsfield Sperm Sexing Technology’ relies on the DNA difference between the X- and Y- chromosomes.

Prior to flow cytometric sorting, semen is labeled with a fluorescent dye called Hoechst 33342 which binds to the DNA of each spermatozoon. As the X chromosome is larger (i.e. has more DNA) than the Y chromosome, the “female” (X-chromosome bearing) spermatozoa will absorb a greater amount of dye than its male (Y-chromosome bearing) counterpart. As a consequence, when exposed to UV light during flow cytometry, X spermatozoa fluoresce brighter than Y- spermatozoa. As the spermatozoa pass through the flow cytometer in single file, each spermatozoon is encased by a single droplet of fluid and assigned an electric charge corresponding to its chromosome status (e.g. X-positive charge, Y-negative charge). The stream of X- and Y- droplets is then separated by means of electrostatic deflection and collected into separate collection tubes for subsequent processing.

While highly accurate, sperm sorting by flow cytometry will not produce two completely separate populations. That is to say, there will always be some “male” sperm among the “female” sperm and vice versa. The exact percentage purity of each population is dependent on the species being sorted and the ‘gates’ which the operator places around the total population visible to the machine. In general, the larger the DNA difference between the X and Y chromosome of a species, the easier it is to produce a highly pure population. In sheep and cattle, purities for each sex will usually remain above 90% depending on ‘gating’, while for humans these may be reduced to 90% and 70% for “female” and “male” spermatozoa, respectively. Some approaches to in vitro fertilization involve mixing sperm and egg in a test tube and letting nature take its course. But in about half of all infertility cases, a problem with the man’s sperm may require a more direct method. In these cases, a different process, called intracytoplasmic sperm injection (ICSI), in which a single sperm cell is injected directly into an egg, is sometimes used. With this one-shot opportunity, it’s important to choose a sperm cell with the best potential for success. A team at the University of Edinburgh, Scotland, has now announced a new technique to ensure that the best sperm win: analyzing their DNA for potential damage beforehand, and choosing those that are structurally sound.

To optimize success rates of IVF, selection of the most viable embryo(s) for transfer has always been essential, as embryos that are cryopreserved are thought to have a reduced chance of implanting after thawing. Recent developments challenge this concept. Evidence is accumulating that all embryos can now be cryopreserved and transferred in subsequent cycles without impairing pregnancy rates or maybe even with an improvement in pregnancy rates. In such a scenario no selection method will ever lead to improved live birth rates, as, by definition, the live birth rate per stimulated IVF cycle can never be improved when all embryos are serially transferred. In fact, selection could then only lower the live birth rate after IVF. The only parameter that could possibly be improved by embryo selection would be time to pregnancy, if embryos with the highest implantation potential are transferred first.

In the majority of human IVF cycles multiple embryos are created after ovarian hyperstimulation. The viability of these embryos, and as a consequence the chance for an embryo to successfully implant, is subject to biological variation. To achieve the best possible live birth rates after IVF while minimizing the risk for multiple pregnancy, one or two embryos that are considered to have the best chance of implanting are selected for transfer. Subsequently, supernumerary embryos with a good chance of implanting are selected for cryopreservation and possible transfer in the future while remaining embryos are discarded.

The best available method for embryo selection is morphological evaluation. On the basis of multiple morphological characteristics at one or several stages of preimplantation development, embryos are selected for transfer. However, with embryo selection based on morphological evaluation implantation rates in general do not exceed 35%, although varying results have been reported. This has resulted in a strong drive for finding alternative selection methods.

The best studied alternative selection method is preimplantation genetic screening (PGS). The classical form of PGS involves the biopsy at Day 3 of embryo development of a single cell of each of the embryos available in an IVF cycle and analysis of this cell by fluorescence in-situhybridization (FISH) for aneuploidies, for a limited number of chromosomes. Only embryos for which the analyzed blastomere is euploid for the chromosomes tested are transferred. Although this method of PGS has been increasingly used in the last decade, recent trials show that it actually decreases ongoing pregnancy rates compared with standard IVF with morphological selection of embryos.

In an effort to overcome some of the drawbacks of PGS using cleavage stage biopsy and FISH, new methods to determine the ploidy status of a single cell are developed, such as comparative genomic hybridization arrays or single nucleotide polymorphism arrays. Furthermore, in an attempt to avoid the confounding effects of chromosomal mosaicism, embryos are now biopsied at either the zygote or blastocyst stage. In addition, increasing time and money are invested in the development of high-tech, non-invasive methods to select the best embryo for transfer in IVF.

This Include metabolomic profiling, amino acid profiling, respiration-rate measurement and birefringence imaging.

  • In metabolomic profiling, spectrophotometric tests are used to measure metabolomic changes in the culture medium of embryos;
  • in proteomic profiling, proteins produced by the embryo and released into the culture medium are identified;
  • in amino acid profiling, amino acid depletion and production by the embryo is assessed using the culture medium;
  • in respiration-rate measurement, the respiration rate of embryos is assessed; and
  • in birefringence imaging, polarization light microscopy is used to assess the meiotic spindle or the zona pellucida.

Embryo donation (also known as embryo adoption) is the compassionate gifting of residual cryopreserved embryos by consenting parents to infertile recipients. At present, only a limited number of such transactions occur. In 2010, the last year for which U.S. data were available, fewer than 1000 embryo donations were recorded. These acts of giving, unencumbered by federal law, are being guided by a limited number of state laws. Moreover, the practice is sanctioned by professional societies, such as the American Society for Reproductive Medicine, subject to the provision that “the selling of embryos per se is ethically unacceptable.” As such, the not-for-profit donation of existing embryos by consenting parents comports with a triad of commonly held ethical attributes. First, donated embryos are not sold for profit. Second, donated embryos are (by original intent) generated for self-use. Third, donated embryos are the product of an unambiguous parental unit and as such are transferable. All told, embryo donation constitutes an established if limited component of present-day assisted reproduction.

Source References:

http://en.wikipedia.org/wiki/Sperm_sorting

http://www.technologyreview.com/news/411706/best-sperm-for-the-job/

http://humrep.oxfordjournals.org/content/26/5/964.long

http://www.nejm.org/doi/full/10.1056/NEJMsb1215894?query=genetics

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Genomics-based cure for diabetes on-the-way

Posted in Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Genome Biology, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on March 4, 2013| 5 Comments »

Reporter: Ritu Saxena, Ph.D.

Diabetes currently affects more than 336 million people worldwide, with healthcare costs by diabetes and its complications of up to $612 million per day in the US alone.  The islets of Langerhans, miniature endocrine organs within the pancreas, are essential regulators of blood glucose homeostasis and play a key role in the pathogenesis of diabetes.  Islets of Langerhans are composed of several types of endocrine cells.  The α- and β-cells are the most abundant and also the most important in that they secrete hormones (glucagon and insulin, respectively) crucial for glucose homeostasis (Bosco D, et al, Diabetes, May 2010;59(5):1202-10).

Diabetes is a ‘bihormonal’ disease, involving both insulin deficiency and excess glucagon.  For decades, insulin deficiency was considered to be the sole reason for diabetes; however, recent studies emphasize excess glucagon as an important part of diabetes etiology.  Thus, insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development.  Increasing the number of insulin-producing β cells while decreasing the number of glucagon-producing α cells, either in vitro in donor pancreatic islets before transplantation into type 1 diabetics or in vivo in type 2 diabetics, is a promising therapeutic avenue.  A huge leap has been taken in this direction by the researchers at the University of Pennsylvania (Philadelphia, PA) in collaboration with Oregon Health and Science University (Portland, OR), USA by demonstrating that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets.  In fact, the treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets.  The research findings were published in the Journal of Clinical Investigation.

Study design: First step was to study and analyze the epigenetic and transcriptional landscape of human pancreatic human pancreatic α, β, and exocrine cells using ChIP and RNA sequencing.  Study design for determination of the transcriptome and differential histone marks included the dispersion and FACS to of human islets to obtain cell populations highly enriched for α, β, and exocrine (duct and acinar) cells.  Then, chromatin was prepared for ChIP analysis using antibodies for histone modifications, H3K4me3 (represents gene activation) and H3K27me3 (represents gene repression).  RNA-Sequencing analysis was then performed to determine mRNA and lncRNA.  Sample purity was confirmed using qRT-PCR of insulin and glucagon expression levels of the individual α and β cell population revealing high sample purity.

Results:

  • Long noncoding transcripts: Long noncoding RNA molecules have been implicated as important developmental regulators, cell lineage allocators, and contributors to disease development.  The authors discovered 12 cell–specific and 5 α cell–specific noncoding (lnc) transcripts, indicative of the valuable research resource represented from transcriptome data.  Recently discovered lncRNA molecules in islets are regulated during development and dysregulated in type 2 diabetic islets.
  • Monovalent histone modification landscapes shared among three cell types:  Monovalent H3K4me3-enriched regions, indicative of gene activation, were identified and compared in α, β, and exocrine cells.  Strikingly, the vast majority of monovalently H3K4me3-marked genes were shared among the 3 pancreatic cell lineages (83%–95%), reflecting both their related function in protein secretion and common embryonic descent. Similarly, a high degree of overlap was observed in H3K27me3 modification patterns in all the three cell types (73%–83%).
  • Bivalent histone modifications (H3K4me3 and H3K27me3) were high in α cells: Bernstein colleagues observed bivalent marks to be common in undifferentiated cells, such as ES cells and pluripotent progenitor cells, and in most cases, one of the histone modification marks was lost during differentiation, accompanying lineage specification (Bernstein BE, et al, Cell, 21 Apr 2006; 125(2):315-26).  α cells exhibited many more genes bivalently marked, followed by β cells and exocrine cells.  Bivalent state was remarkably similar to that of hESC, suggesting a more plastic epigenomic state for α cells.
  • Monovalent histone modifications were high in β cells: Thousands of the genes that were in bivalent state in α cells were in a monovalent state, carrying only the activating or repressing mark.
  • Inhibition of histone methyltransferases led to partial cell-fate conversion: Adenosine dialdehye (Adox), a drug that interferes with histone methylation and decreases H3K27me3, when administered in human islet tissue, led to decrease of H3K27me3 enrichment at the 3 gene loci that are originally expressed bivalently in α cells and monovalently in β cells:  MAFA, PDX1 and ARX.  Adox resulted in the occasional cooccurrence of glucagon and insulin granules within the same islet cell, which was not observed in untreated islets.  Thus, inhibition of histone methyltransferases leads to partial endocrine cell-fate conversion.

Conclusion:  α cells have been reprogrammed into β cell fate in various mouse models.  The reason, as proposed by the authors, might be the presence of more bivalently marked genes that confers a more plastic epigenomic state of the cells that probably drives them to the β cell fate.  Therefore, using epigenomic information of different cell types in pancreatic islets and harnessing it for subsequent manipulation of their epigenetic signature could be utilized to reprogram cells and hence provide a path for diabetes therapy.

Source: Bramswig NC, et al, Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest, 22 Feb 2013. pii: 66514.

Related reading on Pharmaceutical Intelligence:

Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes

Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reprogramming cell fate

CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease – Part IIC

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Genome-Wide Detection of Single-Nucleotide and Copy-Number Variation of a Single Human Cell

SNAP: Predict Effect of Non-synonymous Polymorphisms: How well Genome Interpretation Tools could Translate to the Clinic

Genomic Endocrinology and its Future

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Fertility and reproductive longevity related genes may help dairy producers

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , on March 4, 2013| 1 Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Genomic tools continue to provide new information for dairy producers, and how genomic test results will impact reproductive performance continues to be uncovered. New research findings have uncovered more than 50 genes that could directly impact reproductive traits. Dr. van der Steen discussed about the implications of the research and how it will influence the future of on-farm reproductive decision-making.

The basis for the research, and the source of its considerable competitive advantage, is a genetically superior mouse colony that has been selectively bred for reproductive longevity for more than 25 years, representing more than 30 generations. The selected lines reproduce almost twice as long as the control line and live through 100 percent more pregnancies. This is the result of a gradual accumulation of favorable versions of the relevant genes for reproductive longevity in the selection lines. Using this mouse model, a whole genome scan was recently completed which identified genes and pathways related to reproductive longevity in mice.

The DNA of an individual is like a large library: the information someone is looking for is in some of the books, but it takes a lot of time to read them all. The mouse model has pointed principal investigator Dr. Benkel and his research team in the right direction, so now it is easier for them to find the information they are looking for.

They evaluated 25 genes and found 140 DNA markers that are potentially relevant for the prediction of herd life and fertility in Holstein cows. A second set of 25 genes is being evaluated now. The most promising markers will be further validated in large-scale studies using the DNA from Canadian bulls and from dairy cows from herds in Quebec and Nova Scotia.

Replacement heifers are the second largest cost for commercial dairy producers, so fertility and reproductive longevity have a very significant impact on profitability. Improving this complex of traits offers a highly attractive opportunity to increase productive efficiency and economic returns for producers. A DNA test for Holstein cattle is being developed using the knowledge about fertility and reproductive longevity genes, as well as information on the gene STATA5, which affects embryo survival. The final test, based on a panel of markers, will be able to identify animals with superior breeding values for fertility and herd life at an early age on the basis of a simple laboratory test.

The test results will enable dairy farmers to make decisions on whether to keep or sell heifers, whether to use a cow for the production of replacements, whether to use sexed semen or embryo transfer, and from which bull to buy semen. This knowledge will help them directly improve milk production and reduce herd replacement costs. Selection for fertility and reproductive longevity traits will, over time, increase the overall genetic profile of the herd, leading to additional productivity gains.

Dairy breeding so far has been a black box approach. The more heritable traits were selected without knowing which gene variants are selected and the side effects. This has resulted in a decline of fertility and herd life in dairy cattle.

Genomic selection is an important boost for the overall program, but there is still uncertainty. Progress is faster due to improved accuracy and a reduced generation interval, but the negative impact on fertility and herd life is not directly tackled. The use of a DNA test for fertility and reproductive longevity traits is an opportunity to directly select for gene variants that have a favorable effect on fertility and herd life.

It is important to use the tools that are being developed. Genomic selection will, mainly through the selection of bulls, speed up genetic improvement in general. The use of the more specific genomic testing will allow the producer to reverse the negative genetic trend for fertility and herd life. Use of this DNA test and the use of sexed semen and embryo technology will create opportunities to improve the herd replacement strategy.

It is also important that DNA tests are properly validated in the breed where the test is being used. It is very unlikely that tests work across breeds. Most of the complicated traits such as fertility and herd life will be controlled by a larger number of genes. DNA tests will need to incorporate a majority of these genes in order to have enough predictive power.

Source References:

http://www.dcrcouncil.org/media/Public/Genomics%20undercover%20genes%20related%20to%20fertility%20and%20reproductive%20longevity.pdf

 

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Genetics of Intersexuality (Ambiguous Genitalia): Management of Patients

Posted in Biological Networks, Gene Regulation and Evolution, Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , , , , , , , on February 25, 2013| Leave a Comment »

Intersexuality: Management of Patients

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Introduction

Humans can be immensely strong and adaptable. Certainly some intersexed individuals can, in dignity, maintain themselves in a manner that they neither would have chosen nor in which they feel comfortable — as have others with a life condition from birth that cannot be changed (from cleft palate to meningomyelocele).

Many can adjust to surgery and reassignment for which they were not consulted and many have learned to accept secrecy, misrepresentations, white and black lies and loneliness. People make life accommodations every day and try to better their lot for tomorrow. Many individuals that have come to terms with their life regardless of how stressed or painful.

However, there are individuals who have been given neonatal surgery for cleft palate or meningomyelocele, many of those who have had genital surgery or been sex reassigned neonatally have complained bitterly of the treatment. Some have sex reassigned themselves. Others treated similarly have reasons not to make an issue of the matter but are living in silent despair but coping.

Guidelines

  • In all cases of ambiguous genitalia, to establish most probable cause, do a complete history and physical. The physical must include careful evaluation of the gonads and the internal as well as external genital structures. Genetic and endocrine evaluations are usually needed and interpretation can require the assistance of a pediatric endocrinologist, radiologist and urologist. Pelvic ultrasonography and genitography may be required. Do not hesitate to seek expert help; a team effort is best. The history must include assessment of the immediate and extended family.Be rapid in this decision making but take as much time as needed. Hospitals should have established House Staff Operating Procedures to be followed in such cases. Many consider this a medical emergency (and in cases of electrolyte imbalance this may be immediately so) nevertheless, it is believed that most doubt should be resolved before a final determination is made. It is simultaneously advised that all births be accompanied by a full genital inspection. Many cases of intersex go undetected.
  • Immediately, and simultaneously with the above, advise parents of the reasons for the delay. Full and honest disclosure is best and counseling must start directly. Insure that the parents understand this condition is a natural variety of intersex that is uncommon or rare but not unheard of. Convey strongly to the parents that they are not at fault for the development and the child can have a full, productive and happy life. Repeat this counseling at the next opportunity and as often as needed.
  • The child’s condition is nothing to be ashamed of but it is also nothing to be broadcast as a hospital curiosity. The child and family confidentiality must be respected.
  • In the most common cases, those of hypospadias and congenital adrenal hyperplasia (C.A.H.) diagnosis should be rapid and clear. In other situations, with a known diagnosis, declare sex based on the most likely outcome for the child involved. Encourage the parents to accept this as best; their desire as to sex of assignment is secondary. The child remains the patient. When assignment is based on the most likely outcome, most children will adapt and accept their gender assignment and it will coincide with their sexual identity.
  • The sex of assignment, when based on the nature of the diagnosis rather than only considering the size or functionality of the phallus, respects the idea that the nervous system involved in adult sexuality has been influenced by genetic and endocrine events that will most likely become manifest with or after puberty. In the majority of cases this sex of assignment will indeed be in concert with the appearance of the genitalia. In certain childhood situations, however, such assignment will be counter to the genital appearance (e.g., for reductase deficiency). The concern is primarily how the individual will develop and prefer to live post puberty when he or she becomes most sexually active.

Rear as male:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 1-3)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with extensively fused labia and a penile clitoris

XY individuals with Hypospadias

Persons with Klinefelter syndrome

XY individuals with Micropenis

XY individuals with 5-alpha or 17-beta reductase deficiency

Rear as female:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 4-7)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with hypertrophied clitoris

XX individuals with Gonadal dysgenesis

XY individuals with Gonadal dysgenesis

Persons with Turner’s syndrome

For those individuals with mixed gonadal dysgenesis (MGD) assign male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. The genital appearance of individuals with MGD can range from that of a typical Turner’s syndrome to that of a typical male. Evaluation of high male-like testosterone levels in these cases is also rationale for male assignment.

True hermaphrodites should be assigned male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. If there is a micropenis, assign as male. Admittedly, in some cases a clear diagnosis is not possible, the genital appearance will seem equally male as female and prediction as to future development and gender preference is difficult. There is little evidence a poorly functioning clitoris and vagina is any better than a poorly functioning penis and there is no higher reason to save the reproductive capacity of ovaries over testes. In such difficult cases, whichever decision is made, the likelihood of the individual independently switching gender remains. The medical team in such cases will be taxed to make the best management decision.

  • While sex determination is ongoing, the hospital administration can wait for a final diagnosis before entering a sex of record and Staff can refer to the child as “Infant Jones” or “Baby Brown.” After a sex designation has been made, naming and registration can occur. In those cases mentioned above, where prediction of future outcome is in doubt, parents might consider that a name be used that is appropriate for either males or females (e.g., Lee, Terry, Kim, Francis, Lynn, etc.).
  • Perform no major surgery for cosmetic reasons alone; only for conditions related to physical/medical health. This will entail a great deal of explanation needed for the parents who will want their children to “look normal.” Explain to them that appearances during childhood, while not typical of other children, may be of less importance than functionality and post pubertal erotic sensitivity of the genitalia. Surgery can potentially impair sexual/erotic function. Therefore such surgery, which includes all clitoral surgery and any sex reassignment, should typically wait until puberty or after when the patient is able to give truly informed consent.
  • Major prolonged steroid hormone administration (other than for management of C.A.H.) too should require informed consent. Many intersex or sex reassigned individual’s have felt they were not consulted about their use and effects and regretted the results.
  • In individuals with A.I.S, do not remove gonads for fear of potential tumor growth; such tumors have not been reported to occur in prepubertal children. Retention of the gonads will forestall the need for hormone replacement therapy and possibly help reduce osteoporosis.Furthermore, delaying gonadectomy until after puberty will allow the young woman to come to terms with her diagnosis, understand the reason for her surgery and participate in the decision.
  • Advice regarding gonad removal from true hermaphrodites, individuals with streak gonads and others where malignancies can potentially occur is not so clear. Prophylactically it is common to remove these early; particularly in cases of gonadal dysgenesis.Watchful waiting with frequent checks is always prudent. It is suggested, whenever the gonads are removed, is to explain as best as possible why the procedure is needed and attempt to get consent. If the child is too young to understand the reason for the surgery, its necessity should be explained as early as possible.
  • In rearing, parents must be consistent in seeing their child as either a boy or girl; not neuter. In the society intersex is a designation of medical fact but not yet a commonly accepted social designation. With age and experience, however, an increasing number of hermaphroditic and pseudohermaphroditic individuals are adopting this identification. In any case, advise parents to allow their child free expression as to choices in toy selection, game preference, friend association, future aspirations and so forth.
  • Offer advice and tips on how to meet anticipated situations, e.g., how to deal with grandparents, siblings, baby sitters and others that might question the child’s genital appearance (e.g., “He/she is different but normal. When the child is older he/she and the doctors will do what seems best.”) Parents should minimize the opportunities for such questioning by strangers.
  • Be clear that the child is special and, in some cases might, before or after puberty, accept life as a tomboy or a sissy or even switch gender altogether. The individual may demonstrate androphilic, gynecophilic or ambiphilic orientation. These behaviors are not due to poor parental supervision but will be related to an interaction of the biological, psychological, social and cultural forces to which a child with intersexuality is subject. Some individuals will be quite sexually active and others will be altogether reserved and have little or no interest in sexual relationships.
  • The patient’s special situation will require guidance as to how to meet potential challenges from parents, peers and strangers. He or she will need love and friendly support.Not all parents will be helpful, understanding, or benign and childhood, adolescent, and adult peers can be cruel. Positive peer interaction should be facilitated and encouraged.
  • Maintain contact with family so that counsel is available particularly at crucial times.Counseling should be multi-staged (at birth, and at least again at age two, at school entry, prior to and during pubertal changes, and yearly during adolescence) and it should be detailed and honest. Counseling should be straight-forward, neither patronizing or paternalistic, to parents and to the child as he or she develops with as much full disclosure as the parents and child can absorb. The counseling should ideally be by those trained in sexual/gender/intersex matters.
  • As the child matures there must be opportunity for private counseling sessions and it is essential the door remains open for additional consultation as needed. On the one hand, the full impact of the situation will not always be immediately apparent to the parents or child. On the other hand, they might magnify the developmental potential of the genital ambiguity. As above, the counseling should ideally be by those trained in sexual/gender/intersex matters.
  • Counseling must include developmental sequelae to be anticipated. This should be along medical/biological lines and along social/psychological lines. Do not avoid honest and frank talk of sexual and erotic matters. Discuss the probabilities of puberty such as the presence or absence of menses and the potential for fertility or infertility. Contraception advice may be needed and safe-sex advice is always warranted. Certainly the full gamut of heterosexual, homosexual, bisexual and even celibate options –however these are interpreted by the patient– must be offered and candidly discussed. Adoption possibilities can be broached for those that will be infertile. It is better to discuss these issues early rather than late. Do not obfuscate; knowledge is power enabling the individuals to structure their lives accordingly.
  • The family should be encouraged to openly discuss the situation among themselves, with and without a counselor present, so the child and parents can honestly come to terms with whatever the future holds. Parents have to understand their child’s needs and feelings and the child has to understand the concerns of the parents.
  • As early as possible put the family in touch with a support group. There are such groups for individuals with Androgen Insensitivity Syndrome, Congenital Adrenal Hyperplasia, Klinefelter Syndrome, and Turner’s Syndrome. Intersexed individuals as a whole (hermaphrodites and pseudohermaphrodites of all etiologies) have a support group, the Intersex Society of North America [addresses for these groups are listed below]. It is emphasized that one on one contact with another person having similar experiences can be the most uplifting factor in an intersexed person’s healthy development! Individual groups or chapters might be more inclined toward parental concerns while others might be tilted toward the intersexed person’s concerns. Both perspectives are needed and separate meetings for each faction are useful. Parents need to talk about their feelings in an environment free of intersexed children and adults and the intersexed children and adults similarly need to be able to discuss their feelings and concerns free of their parents. There are times when it is appropriate for physicians to be present and times when it is not.
  • Keep genital inspection to a minimum and request permission for inspection even from a child. Hold in mind that a child may not feel able to deny a physician’s request even though that might be his/her wish. The individuals must come to realize that their genitals are their own and they, not the doctors, parents or anyone else, have control over them. Allow others to view the patient only with his or her permission. Often the genital inspections themselves become traumatic events.
  • Let the child grow and develop as normally as possible with a minimum of interference other than needed for medical care and counseling. Let him/her know that help is available if needed. Listen to the patient; even when as a child. The physician should be seen as a friend.
  • With increasing maturity the designation of intersex may be acceptable to some and not to others. It should be offered as an optional identity along with male and female.
  • As puberty approaches be open and honest with the endocrine and surgical options and life choices available. Be candid at the sexual/erotic and other trade-offs involved with surgery or gender change and insure that any decision finally be that of the fully informed individual regardless of age. To have him/her discuss the treatment with someone who has undergone the procedure is ideal.
  • Most individuals are convinced by the age of 10-15 as to the direction that would be most suitable for them; male or female. Some decisions, however, should be stalled as long as possible to increase the likelihood that the individual has some experience with which to judge. For instance, a female with a phallic clitoris, sexually inexperienced with partner or masturbation, may not realize the loss in genital sensitivity and responsivity that can accompany cosmetic clitoral reduction. Insure that sufficient information is provided to aid in any decision.
  • Most intersex conditions can remain without any surgery at all. A woman with a phallus can enjoy her hypertrophied clitoris and so can her partner. Women with the androgen insensitivity syndrome or virilizing congenital adrenal hyperplasia who have smaller than usual vaginas can be advised to use pressure dilation to fashion one to facilitate coitus; a woman with partial A.I.S. likewise can enjoy a large clitoris. A male with hypospadias might have to sit to urinate without mishap but can function sexually without surgery. An individual with a micropenis can satisfy a partner and father children.There is disagreement as to whether gonads that might prove masculinizing or feminizing at puberty should be removed early on to prevent such changes in a child that does not desire such changes. The disagreement involves the concept that the individual faced with such changes might actually come to prefer them to the habitus of rearing but will only become aware of them post hoc. The bias is to leave them in so any genetic-endocrine predisposition imposed prenatally can come to be activated with puberty. It is admitted that however there is no good body of clinical data from which the best prognosis can be made in such cases. There are some indications, however, that even without the gonads the adrenals might prod pubertal changes.
  • If a gender change is being considered, have the individual experience a real-life living test. In this way the individual will have first hand experience in how it actually is to live in the other role. Experience has shown that most indeed make the switch permanent but some return to their original sex of rearing. Some, usually as adults, will accept an identity as an intersex and plot their own course.
  • Maintain accurate medical, surgical, and psychotherapy records of all aspects of each case. This will facilitate whatever treatment is needed and assist in future research to enhance management of subsequent intersex cases. These records should be available to the patient.
  • Whenever possible, long term follow-up evaluations, e.g., at 5, 10, 15, and even 20 years of age, should become part of the record.
  • Last, it is believed that information and advice may be provided as much as possible but not to be “authoritarian” in the actions. The postpubertal individual must be allowed time to consider, reflect, discuss and evaluate and then, have the last word in his or her genital modification and gender role and final sex assignment.

CASE STUDY

European Congress of Endocrinology 2008

Berlin, Germany
03 May 2008 – 07 May 2008
European Society of Endocrinology

Hypospadias and micropenis in congenital adrenal hyperplasia: a case study

Sandra Fleischer, Ute S Groß, Hjördis HS Drexler, Achim Wüsthof & Heinrich M Schulte

Endokrinologikum Hamburg, Hamburg, Germany.

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases with increased adrenal androgens secretion from the adrenal cortex, characterized by simple virilizing and salt wasting forms. Deficiency of 21-hydroxylase, caused by mutations in the 21-hydroxylase gene (CYP21A2) is the most frequent CAH, accounting for more than 90 percent of CAH cases. Deficiency of 3 beta-Hydroxysteroid-Dehydrogenase Type II is caused by mutations in the HSD3B2 gene and accounts for about 1–10 percent of cases of CAH.

Patient: This report is about a 2-year-old patient of Turkish origin referred to our center with clinical finding of penoscrotal hypospadias and micropenis (stretched penile length 1.5 cm). Testicles were palpable bilaterally in the scrotum. Due to initial biochemical and hormonal findings moleculargentic analysis of CYP21A2 gene was already done, showing heterozygous germline mutations p.Val281Leu, p.Leu307fs, p.Gln318Stop and p.Arg356Trp. His parents are cousin-german to each other.

Methods: Genomic DNA was extracted from peripheral blood leukocytes. Coding regions and corresponding exon-intron boundaries of the CYP21A2 gene and the HSD3B2 gene were amplified by PCR and subjected to direct sequencing.

Results: A compound heterozygous state of these mutations was excluded by sequencing analysis ofCYP21A2 genes of both parents (father has no mutation). Further hormonal studies suggested a 3 β-Hydroxysteroid dehydrogenase type II deficiency and justified sequence analysis of the HSD3B2 gene. A novel homozygous germline mutation (p.Trp355Arg) was found, for which both parents are heterozygous carriers.

Conclusion: To judge a case of CAH in the right way it is important to look at all clinical aspects in a differentiated way. Comprehensive (clinical, biochemical, hormonal) analysis should be conducted and approved by moleculargenetic analysis in line with a genetic counseling.

 

REFERENCES

http://www.ukia.co.uk/diamond/diaguide.htm

http://www.hawaii.edu/PCSS/biblio/articles/1961to1999/1997-management-of-intersexuality.html

Endocrine Abstracts (2008) 16 P589

References on Ethics and Treatment Options:

  1. ^ David A. Warrell (2005). Oxford textbook of medicine: Sections 18-33. Oxford University Press. pp. 261–. ISBN 978-0-19-856978-7. Retrieved 14 June 2010.
  2. ^ Aubrey Milunsky; Jeff Milunsky (29 January 2010). Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. John Wiley and Sons. pp. 600–. ISBN 978-1-4051-9087-9. Retrieved 14 June 2010.
  3. ^ Richard D. McAnulty, M. Michele Burnette (2006) Sex and sexuality, Volume 1, Greenwood Publishing Group, p.165
  4. ^ Elton, Catherine (2010-06-18). “A Prenatal Treatment Raises Questions of Medical Ethics”. TIME. Retrieved 2010-07-05.
  5. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (2010-06-29). “Preventing Homosexuality (and Uppity Women) in the Womb?”. Bioethics Forum, a service of the Hastings Center. Retrieved 2010-07-05.
  6. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (30 July 2012). “Prenatal Dexamethasone for Congenital Adrenal Hyperplasia”. Journal of Bioethical Inquiry. Retrieved 3 August 2012.
  7. ^ Fernández-Balsells, M.M.; K. Muthusamy, G. Smushkin, et al (2010). “Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: A systematic review and meta-analyses”. Clinical Endocrinology 73 (4): 436–444. Retrieved 3 August 2012.
  8. ^ Bongiovanni, Alfred M.; Root, Allen W. (1963). “The Adrenogenital Syndrome”. New England Journal of Medicine 268 (23): 1283.doi:10.1056/NEJM196306062682308.

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Sex determination vs. Sex differentiation

Posted in Chemical Genetics, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation, tagged , , , , , , on February 17, 2013| 1 Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Human sex refers to the processes by which an individual becomes either a male or female during development. Complex mechanisms are responsible for male sex determination and differentiation. The steps of formation of the testes are dependent on a series of Y-linked, X-linked and autosomal genes actions and interactions. After formation of testes the gonads secrete hormones, which are essential for the formation of the male genitalia. Hormones are transcription regulators, which function by specific receptors. Ambiguous genitalia are result of disruption of genetic interaction. This review describes the mechanisms, which lead to differentiation of male sex and ways by which the determination and differentiation may be interrupted by naturally occurring mutations, causing different syndromes and diseases.

 

Sex determination: Initial event that determines whether the gonads will develop as testes or ovaries. Sex is determined by “the heat of the male partner during intercourse” –Aristotle (335 B.C.). Today: both environmental and internal mechanisms of sex determination can operate in different species.

 

Sex differentiation: Subsequent events that ultimately produce either the male or female sexual phenotype. Sexual differentiation is conformed in the human during four successive steps: the constitution of the genetic sex, the differentiation of the gonads, the differentiation of the internal and the external genital tractus and the differentiation of the brain and the hypothalamus.

Sex determination, which depends on the sex-chromosome complement of the embryo, is established by multiple molecular events that direct the development of germ cells, their migration to the urogenital ridge, and the formation of either a testis, in the presence of the Y chromosome (46, XY), or an ovary in the absence of the Y chromosome and the presence of a second X chromosome (46, XX). Sex determination sets the stage for sex differentiation, the sex-specific response of tissues to hormones produced by the gonads after they have differentiated in a male or female pattern. A number of genes have been discovered that contribute both early and late to the process of sex determination and differentiation. In many cases our knowledge has derived from studies of either spontaneous or engineered mouse mutations that cause phenotypes similar to those in humans. How mutations in these genes cause important clinical syndromes and the clinical entities that continue to elude classification at the molecular level have to be tested. Knowledge of the molecular basis of disorders of sex determination and differentiation pathways will continue to have a strong influence on the diagnosis and management of these conditions.

Source References:

http://www.nejm.org/doi/full/10.1056/NEJMra022784

http://en.wikipedia.org/wiki/Sex_determination_and_differentiation_(human)

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Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Drug Delivery Platform Technology, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Imaging-based Cancer Patient Management, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, tagged , , , , , , on February 14, 2013| 7 Comments »

Curator: Aviva Lev-Ari, PhD, RN

Screen Shot 2021-07-19 at 7.16.18 PM

Word Cloud By Danielle Smolyar

A new etiology for Prostate Cancer based on Integrative Genomic Analyses reveals difference in Pathomechanism between Early onset and and Non-Early onset  was reported this week in Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013

Early Onset: Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG

Non Early onset:

Around 65 years of age at onset:  elderly-onset PCAs displayed primarily non-androgen-associated structural rearrangement (SR) formations.

Treatment Comparison for Clinically Localized Primary Prostate Cancer Therapies

Treatment

Description

Selected Risks

Recovery

Selected Outcomes
HIFU – (high intensity focused ultrasound) Minimally invasive use of focused ultrasound waves
to ablate diseased tissue		 Incontinence: 0-10% 1-3
Impotence: 8-50%4,5
Rectal Injury: <3% 4-6		 Catheter worn for
approximately 2-3 weeks; can
return to normal activities
within a few days		 55-95% biochemical
disease-free survival rate at 5 years; 55-98% negative biopsy1-9
Cryotherapy Minimally invasive
procedure using
controlled freeze and thaw cycles to destroy the prostate		 Incontinence: 3-10% 10
Impotence: 40-100% 10
Rectal Injury: 0-3% 10		 2-3 hour procedure with possible overnight stay; return to normal activities within a few days 50-92% biochemical
disease-free survival at 5 years; 87-98% negative biopsy 11,12
Radical Prostatectomy Surgery to remove
prostate, open or
laparoscopic		 Incontinence: 9-20% 13
Impotence: 4-85%13
Rectal Injury:0-5%14		 2-3 day hospital stay, catheter for 2-3 weeks for open surgery; shorter
hospitalization and fewer postoperative complications for laparoscopic procedure		 68–98% biochemical
disease-free survival15,16
External Beam Radiation 6-8 week treatment;
external machine
concentrating radiation
beams to the prostate		 Incontinence: 4-15% 17
Impotence: 41-62% 17
Rectal Injury: 15%17		 Five treatments per week for 6-8 weeks, up to 2 months fatigue after full course of treatment 55–86% biochemical
disease-free survival18-19
Brachytherapy Minimally invasive implants of radiation seeds in the prostate Incontinence: 3-18% 20
Impotence: 14-82% 20
Rectal Injury: 3%21		 1-2 hour procedure with
possible overnight stay		 78–89% biochemical
disease-free survival22

Data presented are for clinically localized, low-high risk primary prostate cancer. The information provided in the chart is therapy and not device specific and may not include all potential risks, recovery and outcome information. For further information please see references.

The Sonablate® 500 is approved for investigational use within the U.S. and is being studied for the treatment of prostate cancer in clinical trials in the U.S. The FDA has made no decision as to the safety or efficacy of the Sonablate® 500 for the treatment of prostate cancer. Currently, the device is available for the treatment of prostate cancer outside the U.S. in more than 30 countries.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxByzdV

Prostate Cancer and Nanotecnology

Dr. T. Barlyia summaried:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

BIND-014 is a programmable nanomedicine that combines a targeting ligandand a therapeutic nanoparticle.  BIND-014 contains docetaxel, a proven cancer drug which is approved in major cancer indications including breast, prostate and lung, encapsulated in FDA-approved biocompatible and biodegradable polymers. BIND-014 is targeted to prostate specific membrane antigen (PSMA), a cell surface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumors.  In preclinical cancer models, BIND-014 was shown to deliver up to ten-fold more docetaxel to tumors than an equivalent dose of conventional docetaxel.  The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumor activity and tolerability.  BIND-014 is currently in Phase 1 human clinical testing in cancer patients with advanced or metastatic solid tumor cancers (NCT01300533). The early development of BIND-014 was funded in part by the National Cancer Institute and the U.S. National Institutes of Standards and Technology (NIST) under its Advanced Technology Program (ATP).

State of the art in oncologic imaging of Prostate

Dr. D. Nir summarizes:

In regards to treatment choice: “active surveillance, focal therapy, radical prostatectomy, and radiation therapy represent a range of treatments with varying degrees of invasiveness for men with different disease grades and stages. Active surveillance and focal therapy, which are relatively new options, are promising but are complicated by uncertainties in risk stratification that affect treatment decision-making, as well as by uncertainties regarding the definition of appropriate outcome measures. Biopsy, which leaves the possibility of under sampling, is not sufficient to resolve these uncertainties. Novel biomarkers and modern imaging are expected to play increasingly important roles in facilitating broader acceptance of both active surveillance and focal therapy. Further research, particularly involving prospective validation, is needed to facilitate standardization and establish the roles of advanced imaging tools in routine prostate cancer management.”

My summary: Prostate cancer is a disease managed by urologists, not radiologists. This disease’s multi-choice of pathways is “craving” for tissue characterization. Nothing could fit the urologist’s work-flow better than ultrasound-based tissue characterization!

Age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. 

Early Onset:

Median age of 47: EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG,

Non Early onset:

Around 65 years of age at onset:  elderly-onset PCAs displayed primarily non-androgen-associated SRs.

Integrative Genomic Analyses Reveal an Androgen-Driven Somatic Alteration Landscape in Early-Onset Prostate Cancer

  • Genome sequencing revealed age-related genetic alterations in PCA
  • Early-onset PCAs display a specific abundance of androgen-driven rearrangements
  • These age-linked alterations coincide with activity levels of the androgen receptor
  • This is an observation of age-specific DNA alterations in a common cancer

Summary

Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions includingTMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.

Early onset prostate cancer tumors tend to have a propensity for containing balanced structural rearrangements, particularly involving genes regulated by the androgen hormone, according to a study in Cancer Cell. As part of the International Cancer Genome Project’s Early-Onset Prostate Cancer project, researchers from Germany and the UK performed whole-genome sequencing on tumor and matched normal samples from 11 individuals who were surgically treated for prostate cancer at a median age of 47 years old. The tumors were also subjected to transcriptome and methylome sequencing.

When they compared sequences from these tumors with sequences from a previously described set of samples taken from seven individuals diagnosed with prostate cancer at around 65 years of age, investigators saw a rise in gene fusion-producing structural changes in the early onset samples.

Those fusions often affected ETS family genes and other genes prone to androgen-related regulation, researchers reported. In contrast, tumors from individuals whose prostate cancer appeared later in life were more apt to contain structural rearrangements affecting genes without any androgen ties.

Follow-up tests using samples from more than 10,000 other patients seemed to support this link between age at prostate cancer diagnosis and androgen receptor rearrangement, study authors said, pointing to a distinct, androgen-driven “pathomechanism” in early-onset forms of the disease.

SOURCE:

http://www.genomeweb.com//node/1191311?hq_e=el&hq_m=1498692&hq_l=5&hq_v=5f2bf80408

Cancer Cell, Volume 23, Issue 2, 159-170, 11 February 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.ccr.2013.01.002

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

REFERENCES

  1. Uchida T, Ohkusa H, Nagata Y, Hyodo T, Satoh T, Irie A. Treatment of localized prostate cancer using high-intensity focused ultrasound. BJU international 2006;97:56-61.
  2. Uchida T, Ohkusa H, Yamashita H, et al. Five years experience of transrectal high-intensity focused ultrasound using the Sonablate device in the treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2006;13:228-33.
  3. Muto S, Yoshii T, Saito K, Kamiyama Y, Ide H, Horie S. Focal therapy with high-intensity-focused ultrasound in the treatment of localized prostate cancer. Japanese journal of clinical oncology 2008;38:192-9.
  4. Ahmed HU, Zacharakis E, Dudderidge T, et al. High-intensity-focused ultrasound in the treatment of primary prostate cancer: the first UK series. British journal of cancer 2009;101:19-26.
  5. Inoue Y, Goto K, Hayashi T, Hayashi M. Transrectal high-intensity focused ultrasound for treatment of localized prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2011;18:358-62.
  6. Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. International journal of urology : official journal of the Japanese Urological Association 2009;16:881-6.
  7. Sumitomo M, Hayashi M, Watanabe T, et al. Efficacy of short-term androgen deprivation with high-intensity focused ultrasound in the treatment of prostate cancer in Japan. Urology 2008;72:1335-40.
  8. Sumitomo M, Asakuma J, Yoshii H, et al. Anterior perirectal fat tissue thickness is a strong predictor of recurrence after high-intensity focused ultrasound for prostate cancer. International journal of urology : official journal of the Japanese Urological Association 2010;17:776-82.
  9. Dudderidge T, Ahmed H, Emberton M. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU international 2009;104:1170-1; author reply 1.
  10. Shelley M, Wilt TJ, Coles B, Mason MD. Cryotherapy for localised prostate cancer. Cochrane Database Syst Rev 2007:CD005010.
  11. Cheetham P, Truesdale M, Chaudhury S, Wenske S, Hruby GW, Katz A. Long-term cancer-specific and overall survival for men followed more than 10 years after primary and salvage cryoablation of the prostate. Journal of endourology / Endourological Society 2010;24:1123-9.
  12. Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. The Journal of urology 2008;180:554-8.
  13. Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA : the journal of the American Medical Association 2009;302:1557-64.
  14. Williams SB, Prasad SM, Weinberg AC, et al. Trends in the care of radical prostatectomy in the United States from 2003 to 2006. BJU international 2011;108:49-55.
  15. Mullins JK, Feng Z, Trock BJ, Epstein JI, Walsh PC, Loeb S. The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. The Journal of urology 2012;188:2219-24.
  16. Loeb S, Zhu X, Schroder FH, Roobol MJ. Long-term radical prostatectomy outcomes among participants from the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam. BJU international 2012.
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  19. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Annals of internal medicine 2008;148:435-48.
  20. Buckstein M, Kerns S, Forysthe K, Stone NN, Stock RG. Temporal patterns of selected late toxicities in patients treated with brachytherapy or brachytherapy plus external beam radiation for prostate adenocarcinoma. BJU international 2012.
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  22. Critz FA, Benton JB, Shrake P, Merlin ML. 25 year disease free survival rate after irradiation of prostate cancer calculated with the prostate specific antigen definition of recurrence used for radical prostatectomy. The Journal of urology 2012.

http://www.internationalhifu.com/treatment-options/treatment-comparison.html?kmas=1&kmkw=prostate%20cancer%20treatment&gclid=CJbo37P0trUCFQdU4AodWhkAxQ#ixzz2KuxrkZbB

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http://pharmaceuticalintelligence.com/2013/02/07/prostate-cancer-and-nanotecnology/

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http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

Genomically Guided Treatment after CLIA Approval: to be offered by Weill Cornell Precision Medicine Institute
http://pharmaceuticalintelligence.com/2013/02/06/genomically-guided-treatment-after-clia-approval-to-be-offered-by-weill-cornell-precision-medicine-institute/

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