Cycles in brain activity could predict seizures in people with epilepsy — Science Translation

Epilepsy is one of the most common neurological disorders affecting 39 million people worldwide. It is estimated that 1% of the population will be affected by the age of 20 and 3% by the age of 75. The random nature of seizures in people with epilepsy can make planning for daily life difficult. Although short […]

via Cycles in brain activity could predict seizures in people with epilepsy — Science Translation

Pancreas Divisum: Diagnosis And Treatment

Pancreas Divisum is a disorder that occurs in the womb when the embryo’s pancreatic parts i.e.  the dorsal and ventral ducts do not fuse to form one main pancreatic duct. Majority of the population do not experience any symptoms. It cannot be prevented but after diagnosis proper treatment is essential. This article elaborates the diagnosis and treatment options. Normally, the digestive juices secreted by the pancreas drain into the small intestine through the ventral duct via the major papilla. Whereas, in pancreas divisum they drain through the dorsal duct via the narrower minor papilla.

Prevalence: It is a widespread disorder with a prevalence of 5-10% in general population in India.

Symptoms: Abdominal bloating, pain, yellowing of skin, nausea, food intolerance, recurrent episodes of pancreatitis.

Diagnosis

Magnetic resonance cholangiopancreatography (magnetic MRCP):
Scanning technique to find two separate pancreatic ducts.
Detailed images of pancreas obtained with MRCP by using a powerful magnetic field and radio waves.
Non-invasive technique
Does not require X-rays
Patient administered with a contrast material intravenously, through a drip. Examination time: Around 10 to 45 minutes

Endoscopic retrograde cholangiopancreatography (ERCP)
A camera and X-ray examination where a tube is passed through mouth into stomach having a small camera at the starting of tube.
Special dye injected which shows up on X-rays
Examination time: Around 15 to 90 minutes.

Treatment
Usually no treatment required.
But if patient experiences pain or pancreatitis increasing the size of minor papilla opening may be suggested. This can be achieved in the following ways:

Medical sphincterotomy: Carried out during endoscopy where the minor duct is identified and cut open.

Surgical sphincterotomy: Here, the surgeon cuts the minor duct using laser and is able to create a large opening for digestive juices to drain out.

Complications:
Major complication is pancreatitis, where medical attention required.
Recurrent or acute pancreatitis, which is very painful and can further lead to malnutrition.
When narrow pancreatic duct are blocked the digestive juices find are difficult to drain into the small intestine which causes swelling and damage of the tissue.
Gradual or sudden pain in the top of the belly, extending to the back. Outlook Pancreas divisum the abnormality which occurs in womb, mostly cannot be prevented.
Majority of people with do not experience any symptoms.
Those impacted by pancreas divisum, need to speak to a doctor about the available treatment options.

Source: Rustagi T, Golioto M, Diagnosis and therapy of pancreas divisum by ERCP: a single center experience, J Dig Dis. 2013 Feb;14(2):93-9.
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Role of Epigenetics in Preservation of Oocytes Through Childhood

Epigenetic modifications established during gametogenesis regulate transcription and other nuclear processes in gametes, but also have influences in the zygote, embryo and postnatal life.

A new research now sheds light on the role of epigenetics in placing egg cells into stasis through childhood. Keeping egg cells in stasis during childhood is a key part of female fertility- a fertilised egg cell is the start of every human life.

Egg cells are created inside a woman’s body even before she is born. They are then kept in stasis throughout childhood until they’re needed as an adult. If egg cells don’t go into stasis they can’t become mature eggs and they will never have the chance to form a new life. And in order to put an egg cell into stasis, biology requires many epigenetic marks throughout its DNA.

Epigenetic marks attached to DNA act as footnotes, indicating which genes are turned ‘on’ or ‘off’. Therefore, the key is to understand where these marks come from in egg cells and how mistakes can cause disease. It is particularly challenging to study epigenetics in egg cells as there are so few of them.

Therefore, a study led by Dr Gavin Kelsey in the Babraham Institute and colleagues in Dresden and Munich, created new, highly sensitive ways to detect epigenetic marks in such small numbers of cells.

Using this approach, they found that, as eggs develop, a mark called H3K4me3 spreads throughout the genome. Scientists have already seen the same mark close to the start of active genes in many cells, but the team discovered that its role in egg cells is different.

A type of epigenetic mark, H3K4me3, spreads through the genome during oogenesis, inducing a transcriptionally silent state. The process is facilitated by the MLL2 protein. In this image, which shows an egg cell within a mouse ovary, DNA is colored blue, epigenetic methylation is colored green, and epigenetic acetylation is colored red. [Courtney Hanna/Babraham Institute]

They demonstrated that the MLL2 protein is responsible for this unusual placement of H3K4me3 in egg cells. Without MLL2, most H3K4me3 marks in egg cells are lost and the cells die before getting the chance to form a new life.

Speaking about the results, first author Dr Courtney Hanna, said: “Our findings show that H3K4me3 is created in two ways. MLL2 can add the H3K4me3 mark without any nearby gene activity while another process, that doesn’t use MLL2, places the same mark around active genes. By studying this new mechanism we hope to expand our knowledge of epigenetics in general as well as adding to our understanding of fertility.

Lead scientist, Dr Kelsey, said: “We are only beginning to unravel the details of the connection between epigenetics and egg development, a fundamental aspect of biology that may play a part in transmitting information from mother to fetus. Discoveries like this highlight some of the unusual biological processes that take place in these highly important cells.

Mechanism Of Intrauterine DHA And AA Transfer

Studies have shown that high levels of DHA are incorporated in the central nervous system and retina during the intrauterine and neonatal period. However, the incorporation level is dependent on the maternal diet. On the other hand, AA present in the inner cell membrane of human vascular endothelium is less dependent on diet. This article provides an overview of the mechanism involved in the incorporation of DHA-AA during the gestation.

There are two main families of long-chain polyunsaturated fatty acids (LCPUFAs) which are called as docosahexaenoic acid (DHA; n-3) and arachidonic acid (AA; n-6) that are essential for overall development. These fatty acids are an integral part of membrane phospholipids, precursors of signalling molecules, and potent activators of gene transcription factors, thus making them essential for overall development. Optimum perinatal intake is necessary to ensure transfer of LCPUFA which may help in appropriate fetal growth and development of immunity. Although there is an acceleration of fetal brain growth during the second trimester, the major accumulation of DHA in the brain occurs during the third trimester and the first year of birth. It has been estimated that the fetal LCPUFA accumulation occurs when the supply of 200-300 mg/day for DHA and 400 mg/kg of body weight for AA per day is available for the de novo synthesis of fetal tissues. A fetus can accrue up to 70 mg DHA per day during the last trimester. A study by Montgomery et al noted that the maternal DHA status significantly increases till mid-trimester and then reduces in the last trimester of pregnancy aiding preferential intrauterine transfer of DHA.

Maternal-Fetal Transfer of LCPUFAs

So far, no report has stated that the synthesis of LCPUFA occurs in the placenta. Humans lack the enzymes required for synthesis of omega-3 (linolenic acid (LA)) and omega-6 (alpha-linolenic acid (ALA)) and thus making them ‘essential fatty acids’ and need supplementation or consumption through food sources. Omega-3 are mainly present in the fish, fish oil and sea mammals and omega-6 can be largely derived from vegetable oils. DHA and eicosapentaenoic (EPA) are produced from alpha-linolenic acid (ALA) through series of desaturation and elongation processes (as indicated in figure 1), whereas linolenic acid (LA) is converted to AA.

Enzymes like delta-5 desaturase (D5D) and delta-6 desaturase (D6D) catalyze the synthesis of LCPUFA in mammals. These two enzymes are encoded by the FADS1/FADS2 genes. Although both desaturases are expressed in most human tissues, the highest expression levels are found in the liver.

Figure 1: Elongation and Desaturation Of LCPUFAs

In Presence Of Enzymes During pregnancy, the pathways for the synthesis of LCPUFAs are upregulated and remain highly efficient to meet maternal and fetal requirements. The ALA to DHA conversion ensures increased accumulation of DHA reserves in the maternal tissue prior to fetal transfer, provided maternal supplementation is optimum. Along with increased maternal metabolic capacity, the rate of placental transfer plays a role in regulating DHA to fetal tissue. Most of the DHA and AA accumulation by the fetus comes from the maternal circulation across the placenta through a facilitated diffusion process. The functional characteristics of the placenta changes to initiate preferential transfer of essential fatty acids during the last trimester of pregnancy.

Mechanism of LCPUFA Transfer and Uptake

Researchers have observed that the transfer of LCPUFA to fetal tissues is selective and occurs via a passive diffusion. A study by Haggarty et al revealed that transport of DHA is preferential over other fatty acids with the selective order of perfusion DHA > AA > ALA > LA. Additionally, recent literature indicates that LCPUFA uptake is regulated by plasma membrane-located transport /binding proteins such as fatty acid translocase (FAT), plasma membrane fatty acid binding protein (FABPpm), the fatty acid transport proteins (FATP) and intracellular FABPs.

Plasma Membrane Fatty Acid Binding Protein Mechanism (FABPpm)

Although FABPpm is a peripheral membrane protein present at several cellular sites, the human placental FABPpm is different from other FABPpm (with respect to pI value, the amino acid composition, fatty acid binding activity and AspAT activity). The placental FABPpm is present in the microvillus membrane of the placenta facing maternal circulation ensuring unidirectional flow of the LCPUFA from the mother to fetus. Studies have indicated the preferential uptake of DHA and subsequent esterification of DHA into triacylglycerol being more efficient over other fatty acids.

Fatty Acid Translocase (FAT) Mediated Transfer

A heavily glycosylated fatty acid translocase (FAT/CD36) is a multifunctional protein involved in angiogenesis, atherosclerosis, inflammation, lipid metabolism, and fatty acid lipid transport. Hence, it has a number of putative ligands including FFA, collagen, thrombospondin and oxidized LDL. FAT has been found in the placental membranes, microvillus, and basal membranes. A number of studies have pointed the presence of a translocational mechanism for preferential LCPUFA uptake.

Fatty Acid Transporter Proteins (FATPs) Mediated Transfer

The third protein which may act along with FAT and FABPpm in the LCPUFA transport process is the fatty acid transport protein (FATP), expressed in several tissues. FATPs is a family of integral transmembrane proteins consisting of FATP 1-6. Of these FATP 1 and FATP 4 in the brain is suggestive of their possible role in LCPUFAs internalization. However, in vitro studies indicate that FATP 1 does not show a preferential uptake for DHA or AA over other fatty acids. Whereas, FATP 4 shows a little higher preference for AA internalization.

Intracellular FABP

The presence of H-FABPs and L-FABPs is observed in human placental trophoblasts. The presence of FABPs in trophoblast is not known but it is hypothesized that the complex interactions of these proteins are essential for fatty acid transport and metabolism in the placenta. Additionally, fatty acid-activated transcription factors (PPARs, LXR, RXR, and SREBp-19) also regulate the fatty acid transport, binding proteins, and placental functions. In conclusion, the human placenta plays a pivotal role in mobilizing the maternal fat stores and channelling important LCPUFAs to the fetus via multiple mechanisms. Studies have indicated that the maternal diet including DHA-AA rich food may impart positive effects on fetal brain and overall growth and development. Whereas, the other benefits of DHA-AA supplementation including prolongation gestation and birth weight of infants are attributed to dosage, timing, and duration of intervention during pregnancy. Hence, future studies are required to study the effects of different amounts of DHA and AA at different stages of pregnancy (in animal models) to provide more insights on the mechanism of fetal transfer and benefits.

References:

Sampath H., Ntambi J. M. 2005. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu. Rev. Nutr. 25: 317–340. Clandinin, M. T., et al. “Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements.” Early human development 4.2 (1980): 121-129.. Simopoulos, Artemis P., Alexander Leaf, and Norman Salem Jr. “Essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids.” Annals of nutrition and Metabolism 43.2 (1999): 127-130. Innis, S. M. “Essential fatty acid transfer and fetal development.” Placenta 26 (2005): S70-S75. Innis SM. Essential fatty acid transfer and fetal development. Placenta 2005;26(Suppl. A):S70e5 Montgomery, Colette, et al. “Maternal docosahexaenoic acid supplementation and fetal accretion.” British Journal of Nutrition 90.1 (2003): 135-145. BELL, STAGEY J., et al. “The new dietary fats in health and disease.” Journal of the American Dietetic Association 97.3 (1997): 280-286. Nakamura, Manabu T., and Takayuki Y. Nara. “Structure, function, and dietary regulation of Δ6, Δ5, and Δ9 desaturases.” Annu. Rev. Nutr. 24 (2004): 345-376. Chambaz J, Ravel D, Manier MC, Pepin D, Mulliez N, Bereziat G. Essential fatty acids interconversion in the human fetal liver. Biol. Neonate 1985;47: 136e40. Haggarty, Paul, et al. “Effect of maternal polyunsaturated fatty acid concentration on transport by the human placenta.” Neonatology 75.6 (1999): 350-359. Duttaroy AK. Transport of fatty acids across the human placenta: a review. Prog. Lipid Res
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