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IPM is an ecosystem-based strategy that focuses on long-term prevention of pests or their damage through a combination of techniques such as biological control, habitat manipulation, modification of cultural practices, and use of resistant varieties. Pesticides are used only after monitoring indicates they are needed according to established guidelines, and treatments are made with the goal of removing only the target organism. Pest control materials are selected and applied in a manner that minimizes risks to human health, beneficial and non-target organisms, and the environment.
Background History
Rice is the most important staple food crop, accounting for 20% in grain yield worldwide. Among the total acreage of rice, Asia shares 90%. Insect pests are the most consistent constraining factors in rice production, especially in the warm and humid Greater Mekong Subregion. Stem borers and rice leaf roller in particular are causing severe yield losses in rice production, often in the range of 10- 20%. The vast majority of rice growers in Southeast Asia use conventional methods of pest control, involving the application of broad-spectrum pesticides. This heavy use of highly toxic plant protection products has led to insecticide resistance in certain pests and caused frequent outbreaks of secondary pests due to the extermination of their natural enemies. The conventional pest management approach not only creates a fragile farming environment by destabilising agroecosystem equilibria, it also poses significant health risks to both farmers and consumers.
The objectives of the project are to ensure agro-ecosystem health, stable and sustainable rice production, and farmer health and consumer food safety in southwestern China, Laos and Myanmar through multi-regional research, capacity building and the implementation of biologically-based pest management suited to the local natural and social conditions and current and predicted climatic conditions.
More specifically, the project aims to establish biological control agent rearing facilities in the target region and to implement Integrated Pest Management practices, based on the produced agents. This training document is supposed to provide relevant knowledge to farmers on the concept of IPM and the identification and management of diseases in Myanmar rice production.
Principles and concepts of IPM
- IPM considers the whole agro-ecosystem including crops, environment, pests and their interactions;
- IPM strongly considers and support naturally-occurring pest control functions and aims to integrate all appropriate measures including cultural, biological and chemical measures;
- Action against any pest problem is only taken when economically and environmentally justified, based on careful monitoring of the crop and considering chemical pesticides only as a last resort;
- IPM emphasizes the growth of a healthy crop with the least possible disruption to agro-ecosystems, reducing or minimizing risks to human health and the environment.
IPM measures
involves careful selection and improvement of farming practices, such as resistant varieties, field sanitation, crop timing and rotation, seed treatment, balanced fertilization, flooding before ploughing, and netted nursery, among others, so as to maintain healthy crops and create adverse conditions for pests to avoid or mitigate pest damage.
is one of the most important components of modern IPM systems. It involves the support/enhancement of naturally occurring and/or the active release of biological control agents to control pests. It is a safe, sustainable and economically viable control measure. It is, however, not always resulting in immediate suppression of pest population like expected from an effective chemical pesticide.
involves the use of chemical pesticides. Pesticides, if still effective, result in rapid control of pests, but most pesticides will also kill beneficial organisms, disrupting natural processes such as pest control. Moreover, pesticide application poses health risks to farmers and consumers, may cause resistance build up in pests and resurgence of secondary pests.
involves an exotic pest which is aimed to be controlled by the introduction of the pest's natural enemies from the country of origin to a new location where they do not occur naturally. In many instances the complex of natural enemies associated with the exotic pest in the country of introduction is inadequate, making the introduction of natural enemies a viable option. However, this method is rarely used in IPM.
involves the supplemental release of natural enemies, boosting the naturally occurring population. Relatively few natural enemies may be released at a critical time of the season (inoculative release) or millions may be released (inundative release).
Involves the conservation or active support of existing natural enemies in an environment. This can be a simple and cost-effective approach because natural enemies are already adapted to the habitat and to the target pests. Cropping systems can be modified to favor natural enemies, such as the introduction of shelterbelts, hedgerows or flower strips which can help ensure the survival of populations of natural enemies. Nectar-rich plants that bloom for long periods are particularly effective, as many beneficial insects are depending on a sugar source during the adult stage.
Biological control agents
they prey upon insect pests, killing them immediately; typical examples are spiders, dragon flies, rove beetles, green plant bugs, lacewings, ladybirds (see below for adult and larval stage), but also frogs or insect-eating birds.
they deposit eggs on or inside insect pests and consume pests in either the egg, larval, pupal or even adult stage. They are often small insects and, due to adults being actively flying and larvae hiding inside hosts, cannot be easily observed on the crop. Below are two pictures showing the typical appearance of parasitoid wasps. An example of a very small egg parasitoid wasp is Trichogramma which is being mass produced in this project (see next page).
they infect and kill insect pests, and comprise of different groups including insect-pathogenic fungi, insect-pathogenic nematodes, nuclear polyhedrosis viruses or bacteria. As the name says they are very small organisms and only become visible when they mass reproduce on an infested host such as in the example below (diseased grub).
Corn crop falls in combat pests / diseases and prevention methods
ဤအချက်အလက်များကိုInstitute of Plant Protection, Chinese Academy of Agricultural Sciences၊ သီးနှံကာကွယ်ရေးဌာနခွဲနှင့် CABI တို့မှပူးပေါင်းပြုစုထားပါသည်။
- Plant Protection Station, Xingan, Guangxi
- Plant Protection Quarantine Station, Dehong, Yunnan
- Plant Protection Centre, Laos
- Tian Yi biological control co. LTD, Hengshui, Hebei
- International Rice Research Institute

subset: commoncrawl


text:
Eloise and Croc
At some point during any one bedroom shack up adventure the question about pets and plants is bound to come up. The wonderful conversations about the pro and cons of a parquet are the things that young relationships thrive on. Over brownies discussing what size cage to get. Morning pillow talk about a newspaper subscription to line the cage. While doing the crossword of said paper deciding we weren't bird in cage type of people; we only bought free range chicken after all. The airy light stuff that people talk about when the only thing that matters is that they're there.
Heather and I's first foray into the adoption of wildlife was a Venus fly trap named Croc. Within three clicks and a credit card we were the new owners of eco-friendly pest control from tedsexoticplants.com. Within days our loft went from boring people keeping storage to exotic jungle in waiting. When it came to Croc, waiting was the word that best described him. Our expectations were Little Shop of Horrors but waiting him to catch anything was the equivalent of staring at the wheatgrass at Booster Juice. We would stare at Croc though, coaching that bastard on for hours. Leaving the screen open letting the bugs in just so the little guy could have a chance. Then we'd end up trying to sleep with the drone of flies in our bedroom and Heather yelling at Croc to do his fucking job. Throwing the odd pillow in his direction. I realized while swatting flies with Wednesday's Trib that I had become Rick Moranis and that movie had more truth to it than I had first realized.
After a few weeks we tried to make Croc a more exciting part of our Swedish bookshelf. We ventured to the flea market and Heather would pick a different pot every week suggesting "Maybe he's just not happy in his home." A new package from amazon was showing up with the paper every couple days with a book on the subject. My personal favorite being John William Wainwright's work circa 1980. Eventually Heather's enthusiasm for Croc dwindled and I was left to watering the little monster; only pure water, tapped and bottled have too many minerals; and feeding him crickets I caught in the park.
Over croissants, the Tribune sitting unread on the table, Heather thought that things in the apartment needed a little more life. She suggested a dog but my social skills were not indicative of walking around the neighborhood everyday leashed to a reason for conversation. A cat was out of the picture because 600 square feet was not nearly enough room for Heather to be sharing with a box of shit. After doing the dishes and throwing the newspaper in the recycle Heather said a fish tank would be a nice addition
I was not thrilled at the prospect of another living organism sharing our resources doing less than a screensaver, but after a Sunday at the aquarium the decision was made and the barrage of amazon boxes began coming to the door again. Books about freshwater fish, saltwater fish, Lake Malawi Cichlids, one about Piranhas I ordered despite Heather's disapproval. We even ordered One Fish, Two Fish, Red Fish, Blue Fish. Croc had to be moved to the top of the fridge to make room for all the fish lit coming daily. In the end we decided to get a Siamese fighting fish named Eloise.
The name Siamese fighting fish sounds like an exotic thing with sharp teeth that small animals and children should stay away from. In reality, they are kind of glorified goldfish. If you are picturing spy killing ninja fish you are way off the mark. Think more like swimming kite, less death agent of the sea. Eloise was a stunning combination crimson red, electric blue and white; like a neon lit American flag floating through the water. He was a great addition to our living space (I never told Heather that Eloise may be genderly confused) and added some life to all the particle board and polyester that made up the rest of the room.
Eloise also brought a new project to us. In the beginning it was just him in his tank with the jade gravel at the bottom. Then a little piece of driftwood Heather had moved around almost nightly to get it just so. Next came the treasure chest that opened and closed letting a glurp of bubbles rise to the top each time. Then he got his castle that he was king or queen of depending on who you asked. Heather spent an entire Sunday afternoon arranging led lights so the mood would be just right for her. After about a year we got a bigger tank, not because King Eloise needed it but Heather insisted that she needed more things.
The average lifespan of a male Siamese fighting fish is three years, females tend to live a few months longer. Eloise surpassed the three year mark by 11 months, and eleven days. She almost made it to the ripe age of four before I found her like old glory, floating, abandon from a ship that had long ago hit bottom. It was just over a year since Heather had mentioned him, and about 2 since The King had received anything new for his realm.
Heather's attention had moved from harboring life in the apartment to other activities. First was pottery. The idea had come to her one day when she was perusing the fridge for nothing in particular and decided that Croc's pot was no longer appropriate. I suggested we go to the flea market that Sunday and find Croc a proper pot. At that she decided that they were all wrong there and would make Croc a pot with her very own hands. And so, books on World War 2 and the human genome were quickly replaced by volumes about pinch pots and glazing. Classes began 2 weeks from then every other Tuesday.
Over the next several months Croc moved bi-weekly into different monstrosities which Heather would bring home. Lopsided coil pots glazed in puce, some kind of vase like thing with heart shaped holes on the side. Then something only the mind of Tim Burton could find beautiful. Her interest eventually dwindled and Croc was left with some kind of cross between an urn and a caesural dish glazed in yellow.
Next came Pilates, then French cooking, Astrology and Scrapbooking. Doing the Sudoku on a Tuesday I realized that I was spending every night with Croc and Eloise except for Wednesday's and Sundays. The next night, I noticed that Heather's tits were bigger over a plate of ratatouille and I knew. On some primal level I'd already known, but when she asked what we were eating, I knew.
The weeks following were kind of a mess. Tribunes piling up on the table, dishes in the sink since Sunday. Still fed red white and blue and pest control, still did the Sudoku, still made dinner every night. But things had definitely changed.
I went to the Flea Market on Sunday solo, Heather had a reading to do. Found castle grey skull for 4 bucks. Bought it and placed Crocs pot on the top floor, covering the knock off corning ware where Croc had been calling home since pottery class ended. Croc that looked like castle grey skull (80s Vintages) Vintage. Heather walked in, asked what it was. I told her I was waiting for a new pot, until then I am the Master of the Universe. She said I was ridiculous and clicked on the TV. She was on her third tour of the 154 episodes of Gilmore Girls.
Enter Eloise.
Death changes everything and Eloise proved that. Enter Heather, coming back from backgammon or sky writing or something wearing the same clothes that she left in minus a sock. She found me reading the sports in the Poang chair, staring at Eloise fluttering in the filter bubbles.
What are you doing? Eloise now spinning around in the current and every heart beat is another spin.
Is that thing dead?
I nodded, taking a gulp of the beer.
I knew you would kill it.
Eloise proved to be the flame that sent the end game in motion. Rocking, rocking watching Eloise flutter
I can't live like this anymore, Christ, you couldn't even take care of her.
Him it's a him.
Take whatever you want.
Then I left. The next 43 hours were a blur. They started at the shithole bar down the block and ended with me on the landlord's couch with my head pulsing and my mouth tasting like the underside of a pool table in a dumpster. I shook the cobwebs out, nodded to Rick, mumbling my appreciation for taking care of whatever the hell happened and made my way upstairs.
I opened the unlocked door and pulled the blinds closed before taking inventory. Gone, three of the four bookcases. Here, all the books from the three bookcases. Gone, stereo. Here, clock radio. Gone, flatscreen, bed. Here, Tiger print Poang chair, sheets from bed. Gone, Heather. Here, me.
Croc was still here but gone were all the pots. Heather had left him in a mound of dirt on top of the fridge taking his pot and Castle Gray Skull with her. Eloise's tank was still here along with her corpse and a note.
Get rid of the fish, clean and drain the tank, be by Tuesday to pick up. Heather
I tried to clean myself up a little (gone, towels, shampoo, toothpaste, here, toothbrush, deodorant, baking soda) put some clean clothes on and sent Eloise to the golden fish bowl in the sky or wherever fish go in the afterlife. I drained the tank, put his things in a box and marked it HEATHER with a green Sharpie.
I took the empty tank down to the parking lot and kicked the front in. I kicked in the sides, I was about to kick in the back when Ruby from 3C came down.
What's going on?
I told her I was cleaning the tank for Heather
That's fucking hilarious. Yeah I saw her cleaning your shit out with a couple of guys yesterday. I was going to ask her about it but she fucking hates me.
It was true. Heather would take the stairs when she saw Ruby in the elevator.
Can I kick the back out?
Did you enjoy my ongoing story so far? Please let me know what you think by leaving a review! Thanks, Nick McDonaldWrite a Review


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by Anonymous
It has been a while since I've knit this pattern but can't remember how to knit 1 purl 1 in same stitch. Can you explain? Thanks
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INFINITI QX60 Lease Terrytown, LA
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People Who Lease Have Good Credit
For some people in Terrytown, LA, the financial aspect of car shopping is the most stressful. If a person's credit is on the low side, it will be difficult to qualify for the vehicle he or she wants. Take a look at your credit score. If you have a score of around 700 or above, you are an ideal candidate for a lease. You'll need a higher credit score for a lease than you would a loan.
People Who Lease Don't Drive as Much
If you enjoy frequent road trips or have long daily commutes, you'll put a lot of miles on your vehicle. This isn't the best scenario if you've got your eye on an INFINITI QX60 lease. The dealer will set a mileage limit of somewhere in the neighborhood of 12,000 to 15,000 miles per year. If you think you'll exceed that and are afraid of paying a penalty, it might be best to take a look at an auto loan instead. However, if you have multiple vehicles and put on less than 1,000 miles per month, a lease could be a great move.
People Who Lease Don't Mind Modification Restrictions
Another potential drawback to leasing is that you can't change the appearance or performance of your car in any way. This means you won't be able to add window tinting, a sunroof, a rear spoiler, curb feelers, or any other elements. However, if these features don't appeal to you as you drive in Terrytown, LA, then you shouldn't shy away from leasing.
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STEARN, Clement Hodgson
B.A. Queens Coll., Cambridge, 1910; B.D. Regent's Park Coll. (London, Eng.), 1912; study at Leipzig, Heidelberg, Hamburg, 1912-3; Ph.D., U. Toronto, 1940.
Class, mstr., Bishop's Stortford Coll., 1919-22; prof, class, dept. head, McMaster U., 1929-54; sec.-treas., pres. CAC, 1959-60; chaplain to H.M. forces, German E. Africa, 1916-17; France, 1917-19.
"Aristophanes and his Audience" (Toronto, 1940).
"A Kalyx-Crater at McMaster University," Phoenix 2 (1948) 37-44; University and Community in the Canadian Democracy (Hamilton, Ont., 1948).
"Clem" Steam's schooling under W. H. D. Rouse at Perse School, Cambridge, invested him with lasting insights into the direct method of teaching Latin and Greek, and with a penchant for grammar and pronunciation. A committed teacher and selfless administrator, a non-publishing scholar, he captivated students with his forays into classical art ("Steam's Urns" was a perennial and cherished offering). His roles as president of the Hamilton Art Gallery and director of extension at McMaster for 16 years helped to win valuable support for the classics from the citizenry and from patrons in Hamilton and the region.
WhWhCan (1951-2) 140; E. T. Salmon, Phoenix 21 (1967) 236.
Alexander G. McKay


text:
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Giving Birth
In America
Giving Birth in America: Florida tells the story of Certified Professional Midwife, Jennie Joseph, as she provides high-quality, personalized prenatal care to women, regardless of their insurance status or birth plans. Naomi is 6 ½ months pregnant and struggling to find health insurance and compassionate prenatal care. Rachel is hoping for a VBAC for her third delivery, but experiences complications with a missed diagnosis and high interventions.


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0518 GMT April 09, 2020
The talks were set to begin on Friday in Doha, but a senior government official in Kabul said "the gathering has been called off for now and details were being reworked", Reuters.com reported.
Afghan delegates scheduled to fly to the Qatari capital on Thursday were told the trip was postponed and new dates were being discussed, a western diplomat in Kabul said.
"The government will have to change the composition of the delegation to make this meeting happen," the diplomat said on condition of anonymity.
Taliban spokesman Zabihullah Mujahid said leaders of the hardline Islamist group were uncomfortable with the size of the Afghan delegation and its composition.
Ghani said Wednesday the 250-member Afghan delegation included some government officials attending in a personal capacity. But the group did not include some of the most powerful figures in Afghan politics, who are reluctant to join forces with Ghani ahead of presidential elections due in September.


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Mid City Subaru Teams up with Chicago Canine Rescue Pet Adoption Event for a "Ruff" Crowd
We had such a great visit from our friends at Chicago Canine Rescue! We gave out #BackedByBerman leashes to some of our local dog lovers. A very special thanks to 101.9 THE MIX Chicago for bringing in extra treats for the canines and goodies for our visitors at Mid-City #Subaru!
Enjoy this short video highlighting some of the amazing canines brought to us last Saturday. Many of these adorable friends are still available for adoption. Please visit chicagocaninerescue.com for more information on adopting or fostering today.


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AddressThai Village Massage and Spa Granville
36 Railway Parade Granville NSW 2142
Phone02 8626 5297
Trading HoursOpen 7 Days
9:30am - 9:00pm
Independent youths in Granville deserve a relaxing treat after an energetic weekend or a busy workday. That's why here at Thai Village Massage & Spa we provide professional massage services that ensure full relaxation and rejuvenation to all our clients.
Whether it's a 30-minute or 2-hour massage, you can experience a relaxing treat that will relieve you from stress and pain. For instance our Traditional Thai massage service help release the blockages and stimulate energy flow. This could contribute to you being energetic again for tomorrow's work or leisure activities.
Other massage services in Granville
Aside from our famous Traditional Thai Massage, we also do the following:
- Foot reflexology
- Thai herbal hot compress massage
- Aromatherapy Thai & hot oil massage
- Deep tissue massage (reaching the deep sections of thick muscles)
- Relaxing hot oil massage
- Pure cocoa body butter massage
- Foot reflexology
- Facial massage & treatment
From head to toe our professional massage services will improve your blood circulation and release the tension built up from work and other activities. Whether it's after a stressful Monday or an exhausting Saturday, we always have something for you.
Contact us for an affordable massage service
Here at Thai Village Massage & Spa we offer affordable services starting at $39 for a 30-minute massage. We also offer Special Packages that best suit each client's requirements or preferences.
From Sunday until Saturday (9:30am to 9pm) we're open to accommodate clients who want to relax and free themselves from the pressures at work. Other clients even choose to celebrate their special day here because they know they deserve a fully relaxing experience.
An excellent massage is known to result to better well-being. The benefits actually go beyond the 30-minute massage session. Other people may notice that you have a different glow even the day after the massage.
It's especially the case with our Facial Massage & Treatment services wherein we can cleanse and revitalise your skin. The face first manifests the stress and tension which is why many clients choose this for quick and noticeable results.
Call us today at 02 8626 5297 if you require a relaxing and professional massage for you, your friends, colleagues and family this weekend or just after work. We're located at 36 Railway Parade Granville NSW 2142.
Services & Prices
Traditional Thai Massage
30mins/$39 | 40mins/$45 | 60mins/$60 | 90mins/$90 | 120mins/$120
Thai massage is an ancient healing art that is based on a concept of invisible energy lines that run throughout the body. Important energy points are located along these lines. The Thai method uses pressure, muscle stretching and compression, done in a rhythmic movement of gentle rocking. Therapists use thumb, palm, elbow, knee and foot pressure, combined with gentle yoga-based stretches to stimulate and balance the energy flow and release blockage, leading to increase vitality and well being.
Foot Reflexology
30mins/$39 | 40mins/$45 | 60mins/$60 | 90mins/$90 | 120mins/$120
Thai Foot Massage, we pressure on reflex points of the feet with Thai balm which can stimulate all the organs and systems of the body. This will improve flexibility and blood circulation, remove toxins in your body, boost your immune system and reduce stiffness.
Thai Herbal Hot Compress Massage
90mins/$135 | 120mins/$170
Thai Herbal Hot Compress massage is the ancient Thai tool that have been used with Traditional Thai Massage for healing any kind of pain and stiff muscle by using more than ten of Traditional Thai herbs which are packed in a cotton bag then compress on energy lines for improving circulation and decrease tension, aches and pains all whole body. We offer you with Traditional Thai Massage or Oil Massage.
Aromatherapy Thai & Hot Oil Massage
30mins/$59 | 45mins/$75 | 60mins/$90 | 90mins/$135 | 120mins/$170
Aromatherapy Thai & Hot Oil Massage is the most popular one, specially blended essential oils enhance the healing effects of this deeply relaxing and soothing therapy. It addresses specific health problems, reduces stress and encourages general well being. We offer 2 choices for you
Deep Tissue Massage
It is a hard and firm's massage that designed to reach the deep sections of thick muscles. Using strong targeted muscle compression, pressure points and isolating muscle groups to address specific conditions and release muscle spasms.
Relaxing Hot Oil Massage
It is a gentle massage that has a calming effect and can be helpful in reducing pain, joint stiffness and improving stress level. Focus on improving general well being and promoting relaxation of mind and body.
Pure Cocoa Body Butter Massage
30mins/$69 | 45mins/$90 | 60mins/$120 | 90mins/$150 | 120mins/$190
Pure Cocoa Body Butter Massage is our ideal of healthy and relaxation that Thai Village Massage and Spa combines massage and beauty together, it is a better choice for ladies and gentleman who want to spend time in massage and deeply moisturizing their skin in the same time. We offer you 2 choices, Deep Tissue & Sport Massage, Relaxing Massage.
Body Butter is enriched with Ivory Coast Cocoa Butter, Shea Butter, Sweet Almond Oil and Wildflower Honey Essence which can nourishes & enriches the skin, improves elasticity & serves as a source of antioxidants, it the skin & gives it a smoother & clearer look, deeply moisturizes the epidermis' top layers, leaving the skin soft & silky smooth. The oil has great nourishing power & helps to prevent the natural loss of moisture.
Facial Massage & Treatment
45mins/$90 | 60mins/$120 (with Mask)
Thai Village massage and spa, we offer you the wonderful facial treatment in our Traditional Thai style, customized to reveal your youthful radiance and revitalize your skin. Our facial treatment includes
Deep cleansing with GALATEIS DOUCEUR-Gentle solftening cleansing fluid face & eyes and GEL ECLAT
Clarifying cleanser pearly foam acts deep down to free skin of toxins and impurities, rich in anti-oxidants.
Facial Scrub with EXFOLIANCE CONFORT smoothing exfoliating cream
delicately eliminates dead cells to encourage skin regeneration and to soften the appearance of fine lines caused by dehydration. It refines the skin's texture and keeps your skin smooth and velvety.
Facial massage with "Collagen Facial Massage Cream
to anti-aging and to calm and rehydrate skin and relieve stress.
Facial Mask with HYDRA INTENSE Hydrating Gel Mask with natural water captors
this can regenerate and protect against the aging process.
Head, neck, shoulder and hands massage.
Ear Candle
Ear candles have been used for centuries to create a sense of well-being and hold a respected place in traditional medicine around the globe, Ear candling is an alternative practice that proponents believe will help remove ear wax, made from 100% beeswax and cotton. This treatment includes Head Neck and Shoulder Massage.
Packages 2 Hours
Gold Package $199
Pure Cocoa Butter or Aromatherapy Thai & Hot Oil Massage 1 Hour + Facial Massage 1 Hour
Silver Package $159
Thai Herbal Hot Compress Massage 1.5 Hour + Foot Reflexology 30 Minutes
Bronze Package $149
Pure Cocoa Butter or Aromatherapy Thai & Hot Oil Massage 1 Hour + Traditional Thai Massage 1 Hour


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Panic Miracle System
For more than 40 years, epidemiological studies have clearly demonstrated a tendency for diseases such as schizophrenia, bipolar disorder and autism to run in families. Thus it has been shown that such disorders are much more frequent in close relatives of patients than in the general population. For example, estimates of the increased risk of suffering from the disorder if the patient has a sibling with the disorder range from nine- to eleven-fold for schizophrenia and about sevenfold for those with bipolar disorder. These major psychiatric disorders show a significantly greater concordance rate in genetically identical twins. Thus the concordance rate for monozygotic twins in schizophrenia is approximately three times that observed in dizygotic twins. In bipolar disorder, the corresponding concordance rate is approximately eight times greater in monozygotic than in dizygotic twins. From such studies it has been calculated that between 60 and 80% of the liability of these two disorders is genetic in origin. However, it must be emphasized that these calculations do not identify specific genetic causes for the conditions but they do demonstrate that the genetic, as well as environmental components, play a significant role.
The question arises regarding how the genes that contribute to major psychiatric disorders can be identified. Many of the medical conditions for which a genetic component has been identified follow a genetic pattern that clearly follows classical Mendelian inheritance. For example, in cases of Huntington's disease and cystic fibrosis, the two parents who carry the recessive gene give rise to offspring in the ratio of 1:2:1, one expressing the disease, two not showing the symptoms but carrying the gene and one not carrying the gene for the disorder. Such conditions follow the Mendelian pattern of inheritance because the condition is caused by a mutation of a single gene. While the locating of the underlying gene in such situations is often difficult and time-consuming, the techniques of classical molecular genetic analysis, and linkage studies followed by positional cloning, are now well established. For monogenic diseases such as Huntington's, a common pattern emerges in which a single gene, or small number of genes, that may harbour a number of rare mutations can be identified. Each mutation alone is then sufficient to produce a phenotype of the disease.
Regarding bipolar disorder and schizophrenia, while there is some evidence that some families transmit the risk of the disease in a Mendelian fashion, the overall pattern of disease transmission is complex and it is unlikely that these conditions are due to a single gene. This suggests that there may be multiple genes involved, either many genes with strong alleles or common variants in many genes, each of which increases the risk of the disease in a modest way. An example of this would be Alzheimer's disease, in which significant associations have been demonstrated between apolipoprotein (APO) E4 and the occurrence of the disease. An account of the genetic basis of Alzheimer's disease can provide a useful example of the relationship between the genetic basis and the expression of the disease.
Alzheimer's disease exists in two major forms, the so-called early and late onset types. The former follows typical Mendelian inheritance while the latter shows a more complex, non-Mendelian, pattern of inheritance. The early onset form of the disease has permitted the identification of several genes which are causally related to the condition.
In the elderly, in which Alzheimer's disease has been estimated to occur in up to 20% of those aged 80 years, it has been shown that one allelic form of APO E is associated with an increased risk for developing the disease. Of the three APO E allelic forms in man, APO E4 is associated with the late onset form of the disease; this may account for up to 50% of the genetic risk for the late onset form whereas those carrying the less frequent E2 allele appear to be protected from the disease.
In the early onset familial form of the disease, affecting approximately 5% of cases, there is a clear autosomal dominant pattern of inheritance. Mutations in three genes have been identified involving the beta amyloid precursor protein, presenilin-1 and presenilin-2. The function of these proteins is described in more detail in the chapter on the dementias (Chapter 14). It has been estimated that mutations in these genes account for approximately 50% of the cases of the early onset disease.
Summary of methods used to detect possible genetic defects in psychiatric disorders
The genetic basis of late onset Alzheimer's disease conforms to the common disease-common variant hypothesis which states that genetic susceptibility is attributable to common variants present in the population at a high frequency. Significant associations have been demonstrated between several common polymorphisms such as APO E4 and Alzheimer's disease, already referred to. Individuals differ from each other at many positions across the genome and a variation at a particular nucleotide is called a polymorphism. It has been calculated that approximately one nucleotide base in every 1000-2000 nucleotides differs between chromosomes. If, as seems likely, the common disease-common variant hypothesis applies to schizophrenia and bipolar disorder then it may be essential to undertake association studies which follow the inheritance of a gene within a population rather than within families. Association studies test if a polymorphism is more frequently found in those with the disease (called ''cases'') than in normal individuals (controls). In such tests, the transmission of a polymorphism from a heterozygous parent to an affected offspring is followed. If the polymorphisms are not associated with the disease, then the rate of transmission from parent to affected offspring in a population will be 50%. Significant deviations from this predicted transmission rate indicate a possible association with the disease. Such studies are an attractive means to understanding complex psychiatric diseases because they have the power to identify causal associations between a particular allele and a heterogeneous disease and do not require the collection of large pedigrees containing multiple affected individuals. However, for such a method to be applied, the polymorphisms used in the assessments must have been identified. This necessitates the collection of a large group of polymorphisms to form a library of potential disease-causing alleles. Traditionally techniques for the detection of polymorphisms have involved gel-based screening methods or direct DNA sequencing of numerous individuals. Such methods are laborious and time-consuming. Microarray technology has revolutionized the approach by developing DNA microchips that contain a high density of oligonucleotides which are capable of rapidly detecting variations in nucleotide sequences. Micro-arrays consist of microchips of DNA attached to the surface of a solid support that may vary according to the density and the form, or size, of the DNA on the surface. There are different commercially available forms of microarray chips and the presence of many independent DNA molecules on the chip surface allows hybridization of many different species simultaneously and for the results to be similarly detected on a microscope slide. By labelling the final products formed with a fluorescent dye, the resulting hybridization pattern can be detected by a confocal microscope.
The major question which arises now that the technology for rapid screening has become available is which genes should be chosen? If the possible cause of the disease is known then the answer is clear. However, for most of the major psychiatric disorders the causes are unknown although neurochemical, neurodevelopmental, autoimmune and environmental factors are probably involved. For this reason, association studies in schizophrenia and bipolar disorder have focused on genes related to the dopaminergic and serotonergic systems. Unfortunately, polymorphisms related to these genes have not convincingly been found to be associated with schizophrenia or bipolar disorder. However, several other lines of evidence suggest that schizophrenia may be a neurodevelopmental disorder in which the frontal association cortex, an area responsible for several important high-level functions, has been shown to be malfunctional. Thus schizophrenia may result from a disorder of neuronal migration. If so, the discovery of polymorphisms in genes that regulate cortical development could prove to be a useful area of investigation. This approach has already identified the gene dsh (dishevelled, named after a gene identified in the fruit fly, Drosophila) in the mouse which, when absent, leads to a reduction in the startle response. Prepulse inhibition, the reduction in the startle that the animal shows to a previous stimulus, has been shown to be diminished in patients with schizophrenia. While it is premature to propose that dsh deficient mice are a model for schizophrenia, such findings do suggest that such genes may play an important role in the early differentiation of the brain. During the normal development of the brain, a large number of genes are activated and become involved at different times and have different functions. In the early pattern formation of the brain, during the development of the neural tube, the homeotic genes (the so-called hox family genes) encode for transcriptional factors that bind to DNA and thereby regulate the expression of other genes. This process is believed to convey information on dorsoventral positioning to the cells of the developing neural tube. However, there is evidence that a mutation in a homeobox gene is associated with gross brain defects which makes it unlikely that a mutation in the early genes could be responsible for the subtle changes found in schizophrenia.
There is evidence that the cortex of the brain of schizophrenic patients contains neurons that are in abnormal positions when compared to non-schizophrenic individuals. This suggests that the migration of neurons may be abnormal during the developmental period. The neuronal cell adhesion molecule (NCAM) is an immunoglobulin that mediates adhesion between neurons, thereby exerting a key role in morphogenesis, differentiation and the migration of neurons. NCAM is encoded by a single gene that undergoes alternative splicing to generate several alleles which exhibit different spatial and temporal patterns of expression in vertebrates. The NCAM gene is located on chromosome 11 and two polymorphisms are known to occur in the NCAM gene region. However linkage analysis of 71 families has failed to confirm that an abnormality in the NCAM gene occurs in schizophrenia.
During brain development, neurons send out numerous dendrites in which growth factors play a prominent part. The neurotrophins comprise a family of structurally and functionally related growth factors that include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and the neurotrophins 3 and 4/5. These peptides cause neuronal growth, increase the size of the body of the neuron and maintain the survival of the neurons of the dopaminergic, serotonergic and glutaminergic systems. As a decrease of 20-30% in BDNF mRNA has been reported to occur in the hippocampi of schizophrenic patients, it seems possible that a defect in this growth factor could be responsible for the occurrence of smaller neurons in these patients. The BDNF gene is located on chromosome 11 and preliminary findings from 72 nuclear families suggest that the frequency of the A2 allele is significantly higher, and that of the A1 allele significantly lower, in schizophrenic patients. The NT-3 gene, located on chromosome 12, and the promoter region of this gene contain a highly polymorphic marker yielding at least 11 dinucleotide repeat alleles. Of the case-controlled association studies undertaken so far, abnormal alleles have been reported in two of the five studies.
Lastly, studies on the different polymorphic forms of the synapsins, that organize the mobilization of neurotransmitter vesicles thereby regulating neurotransmitter release, could account for some of the subtle changes in neurotransmission that occur in schizophrenia. However, to date linkage analysis studies have failed to reveal any positive associations between the various polymorphisms of the synapsin gene and schizophrenia.
The genetic basis of obsessive-compulsive disorder (OCD)
There have been over 18 family studies of OCD during the past 70 years but, due to methodological differences, the familial aspects of the disorder remain controversial. Family studies look for the prevalence of the disorder among the biological relatives of the probands (i.e. individuals who are affected by OCD) and the prevalence is then compared with that seen in the general population or in a control group. The latter are usually unaffected subjects or relatives of those with OCD. Despite the limitations of the studies, most have found a significant increase in the rates of OCD among the first-degree relatives of the probands when compared with the general population. Similarly, there is evidence from family studies of patients with chronic motor tics and Tourette syndrome that the rates of these conditions, and OCD, are higher among the relatives of patients with Tourette syndrome. More recent studies have suggested that some of these cases are familial but unrelated to tics while in other cases there appears to be no family history of either OCD or tics.
Twin studies comparing mono- and dizygotic twins have shown concordance rates of between 25 and 87%, depending on the study. Since none of the studies show a concordance rate of 100%, it is clear that non-genetic factors must influence the expression of OCD.
Linkage analysis studies, in which the OCD is linked to a known polymorphic marker, are used to determine if there is a single gene locus causing susceptibility for the disorder. Using such an approach for a battery of candidate genes coding for receptors and enzymes involved in dopaminergic and serotonergic transmission (i.e. for the two neurotransmitters most likely to be involved in OCD), no evidence was found for a link.
Association studies have proven to be more fruitful. In such studies, the allelic frequencies for specific marker genes are compared with a control population. When OCD patients were investigated for the association of tics with the dopamine receptor 2 marker it was shown that there was an increased frequency of homozygosity for the allele A2 of TaqIA at the D2 receptor locus. Not all investigators could replicate this finding however. No positive associations have been found between OCD and the D3 gene while there was some association found between OCD with tics and the D4
gene. Two other catecholaminergic markers have been investigated in patients with OCD. Thus a positive association has been reported between the low activity allele of catechol-O-methyl transferase in male patients and a higher frequency of the low activity allele of monoamine oxidase type A gene in female patients. There is also evidence that the serotonin transporter gene is abnormal. In conclusion, evidence from genetic studies lends support to the view that a single gene defect occurs in patients with OCD while association studies of candidate genes, in spite of methodological difficulties, have highlighted the loci for D2 and D4 receptor genes together with those for catechol-O-methyl-transferase and monoamine oxidase A.
Studies assessing the diagnosis of panic disorder by the direct interview of family members, a method commonly employed in the 1980s, showed that the risk of developing the disorder is higher in the first-degree probands. This has been estimated to be 17% for first-degree relatives compared to 2% for the control population. In addition, relatives of probands had a higher prevalence of generalized anxiety disorder and major depression. This was confirmed in another study of anxiety disorders in female relatives and showed a morbidity risk for all anxiety disorders to be 32% among first-degree relatives of agoraphobic patients with panic attacks and 33% in those with panic disorder. The risk was found to be even greater in the offspring when both had anxiety disorders. Overall, family studies have shown that first-degree relatives of probands with panic disorder have a three- to 21fold higher risk of developing panic disorder than first-degree relatives of healthy probands.
The relationships between panic disorder and other types of anxiety disorder have also been the subject of study. Thus some investigators have reported that relatives of those with agoraphobia have a higher risk for the disorder than relatives of patients with panic disorder, leading to the suggestion that agoraphobia should be considered a more severe form of panic disorder which has an independent genetic transmission. Other studies, however, have found that the diagnosis of separation anxiety and agoraphobia in probands increased the risk of both panic disorder and agoraphobia in the relatives of the patients. Such observations support the hypothesis that panic disorder and agoraphobia are two phenotypic expressions of the same condition due to a different degree of genetic penetrance.
The analysis of the relationship between panic disorder and major depression has produced conflicting results. The possible link between these disorders has been provided by the frequent occurrence of major depression in patients with panic disorder and agoraphobia, both conditions responding to antidepressant treatments. Whereas most of the genetic analyses available suggest that there is an independent genetic basis for these conditions, it is noteworthy that relatives of patients with both panic disorder and agoraphobia are more likely to develop depression, phobias and alcoholism when compared with relatives of probands with panic disorder alone. There does not appear to be an association between generalized anxiety disorder and panic disorder, suggesting that they are separate entities. Generalized anxiety disorder appears to be more prevalent (approximately 20%) in relatives of probands with the disorder than in those of relatives with panic disorder (5%) or agoraphobia (4%).
Twin studies have demonstrated only a moderate concordance in monozygotic versus dizygotic pairs. Using the hypersensitivity to carbon dioxide as a challenge test, it has been shown that there is a significantly higher concordance rate in monozygotic (56%) than in dizygotic (13%) twins.
In recent years, emphasis has tended to switch from family and twin studies to molecular genetics. Linkage analysis in families with a psychiatric disorder has often proven to be a fruitful method to determine the degree of inheritance of a disorder. The method of parametric linkage estimates the likelihood of the distribution of genetic markers of an illness by a predetermined model and expressed as the logarithm of the odds score (the so-called lod score). For simple Mendelian inheritance of a disease, a lod score of 3.0 or greater, obtained by scanning the genome for markers of the disease, is considered to be a statistically significant linkage. However, most psychiatric disorders do not follow classical Mendelian genetics so such an approach is of limited value. For this reason, other linkage methods have been developed. For example, the allelic-sharing method is based on detecting the frequency of the inheritance of the same genetic marker from each parent. The presence of a gene that causes the disorder is revealed when the allele that is shared between the siblings is greater than 50%. To date, all the linkage studies in panic disorder have been inconclusive. Neither has the search for candidate genes for neurotransmitters (for example, GABA, tyrosine hydroxylase, serotonin receptors, dopamine receptors, adrenoceptors, opioid receptors) proven to be any more fruitful. However, there is some preliminary evidence for an association between the cholecytokinin (CCK) promoter gene and panic disorder which, if replicated, would support the hypothesis that the CCK-B receptor is hypersensitive in panic disorder. This is discussed in more detail in Chapter 9.
Genetics of attention deficit/hyperactivity disorder (ADHD)
ADHD is the most common psychiatric disorder with onset in childhood. The condition is characterized by inattention and/or hyperactivity and impulsivity which is associated with cognitive, social and academic impairments. It has been estimated that in up to 60% of patients, these impairments persist into adulthood. Males are affected more than females (4:1).
ADHD is a familial disorder with a population-based prevalence of about 10% and a prevalence rate in siblings of approximately 25%. Detailed studies of the disorder suggest that there is a five- to sixfold increase in first-degree relatives of affected persons. However, as with other psychiatric disorders, the finding of familial aggregation alone does not necessarily lead to the conclusion that the disorder is of genetic origin as such studies do not separate genetic from environmental factors.
Twin studies have been useful in discriminating the genetic from environmental factors. The concordance rate for monozygotic versus dizygotic twins has been estimated at 51% and 33% respectively, and it has been estimated that approximately half the variance in the trait factors of hyperactivity and inattentiveness are accounted for by the genetic basis of the disorder. There is evidence that, in ADHD, there is an incompletely penetrant autosomal-dominant gene; the penetrance of the gene being calculated as 46% in boys and 31% in girls.
Molecular genetic studies have been particularly fruitful in evaluating the neurochemical basis of the disorder. Genes involved in the dopaminergic system were considered to be important as the most effective symptomatic treatment of the condition has been methylphenidate and dextroampheta-mine, drugs which potentiate the release, and inhibit the reuptake, of dopamine. In addition, the involvement of dopamine in ADHD is further implicated by the increased vulnerability of these patients to drug abuse. As discussed in Chapter 15, the dopaminergic system has been implicated in reward mechanisms so the search for abnormalities in the genes encoding for different aspects of them seems a reasonable start.
Of the genes for the dopamine receptors which have been studied, the candidate gene for the dopamine D4 receptor has been shown to be positively associated with ADHD. However, not all investigators have verified this finding.
One of the major limitations in studies of the genetics of behavioural disorders in children arises from the overlap with other conditions. For example, nearly 50% of the patients with ADHD also have co-morbid conduct disorders. In addition, a subtype of the disorder may exist in those children in which the disorder persists into adulthood. An additional problem arises from the overlap between ADHD and bipolar disorder; this has been estimated to be as high as 16%.
In CONCLUSION, although positive genetic studies have been reported and subsequently replicated, the results must be treated with caution as they are based on small sample sizes with restricted statistical power and complicated by co-morbid illnesses. Nevertheless, preliminary evidence suggests that ADHD, like many major psychiatric disorders, does have a genetic basis.
The impact of molecular neurobiology on psychopharmacology: from genes to drugs
About 150 years ago, Charles Darwin observed that ''those who make many species are the 'splitters', and those who make few are the 'lumpers' ''. Today, the ''splitters'' dominate research in the life sciences. Such researchers can generate massive quantities of data on genes and their networks, proteins and their pathways and the numerous cascades of messenger molecules that ultimately result in a physiological response. Technological progress in recent years has enabled the genome of species as diverse as the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster to the mouse and man to be unravelled, thereby opening up the possibility not only of identifying genes that are responsible for physiological processes but also those that are aberrant and cause genetically based diseases.
Few would deny the importance of such research, but the very success of the ''splitters'' has had a seriously detrimental effect on the equally important role of the ''lumpers'', who attempt to integrate the molecular/cellular approach with the behavioural/psychological consequences. As a consequence, the ''lumpers'' are becoming a threatened species of researchers. There are several reasons for this, not the least of which is the widespread opposition to vivisection and the lack of training in behavioural pharmacology in university courses. As a consequence, research (and funding for behavioural research) has declined in prestige. This has had an adverse impact not only in areas of basic life science research but also in the pharmaceutical industry where the ultimate validation of the therapeutic potential of a new molecule depends on behavioural pharmacology. As a senior neuro-pharmacologist has recently remarked ''Many can genotype but few can phenotype''.
Despite this unfortunate disparity between molecular neurobiology and behavioural pharmacology, it is essential that the neuropharmacologist and biological psychiatrist are fully conversant with the basic concepts of the subject in order to appreciate both its success and limitations.
Pick up any intelligent newspaper or magazine, view any television programme dealing with the life sciences or medicine, and the impact of cloning is likely to be discussed. To understand the basis of cloning, it is necessary to consider how bacteria have evolved to resist infection by external sources of genetic material. It has long been recognized that if a virus could infect one strain of bacteria, it could then also infect other bacteria of the same strain but not those of a different strain. Thus virus infection was shown to be restricted to a particular strain, a restriction now known to be due to two classes of enzyme, namely the methylases, which modify bacterial DNA marking them as ''self'', and the destruction enzymes, which act as molecular ''scissors'' and can destroy foreign DNA.
Restriction enzymes are sequence-specific in that they cut DNA at specific locations along the nucleotide chain. While some of these enzymes yield ''blunt'' ends to the resulting DNA fragment, others make staggered cuts in the DNA chain to produce ''sticky'' ends. Over 250 restriction enzymes are now commercially available.
Cloning would not be possible without restriction enzymes. DNA chains with a ''sticky'' end act like molecular ''Velcro'', thereby enabling two pieces of DNA with complementary nucleotide sequences to be joined together. The linking of the DNA strands is brought about by the enzyme DNAligase which permanently joins the assembled DNA sequences with covalent bonds, thereby producing a recombinant DNA molecule.
The next stage is to ensure that the recombinant DNA molecule is copied by the enzymes which synthesize nucleic acids. These DNA and RNA polymerases synthesize an exact copy of either DNA or RNA from a pre-existing molecule. In this way the DNA polymerase duplicates the chromosome before each cell division such that each daughter cell will have a complete set of genetic instructions which are then passed to the newly formed RNA by RNA polymerase. While both DNA and RNA polymerase require a preformed DNA template, some viruses (such as HIV) have an RNA genome. To duplicate that genome, and incorporate it into a bacterial or mammalian cell, the viruses encode a reverse transcriptase enzyme which produces a DNA copy from an RNA template.
Thermostable DNA polymerases have now been produced for polymerase chain reaction (PCR) studies in which specific segments of the DNA molecule can be mass produced from minute quantities of material. RNA polymerases are then used to create RNA transcripts from cloned genes in vitro. Reverse transcriptases have their specific uses in molecular biology. These enzymes are used to form ''cDNA libraries'' which are batteries of molecules each one representing a single gene expression. Such DNA libraries can then be analysed to determine which genes are active under different conditions and in different tissues. cDNA libraries are now used experimentally in microarray assemblies to detect gene changes following drug treatment. This will be discussed further later in this chapter.
In a typical experimental situation, the gene of interest is incorporated into a plasmid, which is a natural vector used by either a bacterium or other cell type. To transfer the DNA fragment of a gene, the plasmids are digested with one or two restriction enzymes and the desired fragment joined into a single DNA recombinant molecule using DNA ligase. To express the new gene in vitro, the plasmid containing the recombinant DNA is then incubated with an RNA polymerase to form new RNA which is then used to programme an in vitro system which translates the information necessary for the synthesis of a new protein.
The foregoing is only intended to give a brief overview of the mechanisms behind cloning. So far, the impact on diseases in man has been limited to experimental approaches to the treatment of cystic fibrosis and rare conditions in which a recessive gene is responsible. However, cloning techniques have provided important information in producing animals, usually mice, which have been manipulated to express or remove genes that are implicated in psychiatric disorders. Such ''knock-out'' and ''knock-in'' mice now provide important information in which specific genes can be studied for their effects on behaviour, which may ultimately be an important contribution to understanding the genetic basis of psychiatric and neurological diseases.
Genetically modified mice and their importance in psychopharmacology
Just as adding genes from a complex to a simpler organism (for example, from man to a fruit fly) may be helpful in understanding the function of a gene, so it may help to understand how a gene functions by eliminating it. To date, most gene ''knock-out'' studies have been undertaken in mice because of:
(a) the relative ease with which genes can be manipulated and eliminated;
(b) the relatively rapid rate at which mice breed;
(c) their well established and relatively complex behaviour.
The success, and also the limitations of the gene elimination strategy can be illustrated by studies on the molecular basis of memory and learning. In the early 1980s it had been shown that the glutamate NMDA receptor was an essential component of memory formation, the term ''long-term potentia-tion'' (LTP) being applied to the molecular mechanism involved. The drugs which were then available were limited in their specificity for the NMDA receptor but by selectively deleting genes thought to be involved in memory it was possible to identify the precise components of the NMDA-linked messenger complex located in the hippocampus. Further studies enabled genes ranging from those encoding neurotransmitter receptors, protein kinases and transcription factors to be identified. However, there are limitations to these techniques which should be considered.
A major problem with ''knock-out'' technology relates to the need to delete the gene at the very early stage of embryonic development. Often this results in the death of the neonate. Even if the gene is not essential for survival, it could have a key role to play in development that is unrelated to neuronal plasticity. Thus the deficits in learning and memory seen in the mature mouse could be the result of a developmental defect rather than a specific abnormality in the NMDA receptor complex. Alternatively, the deletion of a gene that from experimental studies might be expected to have a major effect on learning and memory in practice may have no apparent effect. This is due to the mechanism of compensation whereby other genes take over the function of the deleted gene.
Thus developing ''knock-out'' mice to understand the function of a particular gene gives little information on the timing when the gene becomes active. Nor does it necessarily reflect the location of the gene in the intact (wild-type) mouse or indeed, the long-term effect of the nervous system on its function. Nevertheless, these are largely technical drawbacks that will undoubtedly shortly be solved. In principle, studying the actions of psychotropic drugs on genetically modified animals will allow the detrimental effects of a deleted gene on the general health of the animal to be avoided. Such an approach will also allow investigations of the interactions between neuronal signalling pathways by assessing the synergistic interactions between the behavioural and other biological effects of the deleted gene and drugs.
Virtually every physical and psychiatric disorder has a genetic component. However, the vast majority of these diseases have a complex pattern of inheritance and there is no evidence that a single genetic locus is responsible for any of the major psychiatric disorders. Rather it appears that multiple alleles (gene products) occurring at multiple sites within the genome interact to produce a vulnerability to the disorder. The enthusiastic reception for the unravelling of the human genome rests largely on the promise that it will soon lead to an understanding of the pathological basis of most diseases which, in turn, will aid the development of more effective therapeutic treatments.
Following the sequencing of the human genome it was found that there were between 30 000 and 40 000 genes that code for proteins, only twice as many as occur in the fruit fly or the nematode worm! However, it does appear that human genes are more complex than those of flies and worms in that they generate a large number of proteins due to the alternative ways of splicing the molecules. Hopefully knowledge of the human genome will enable genes to be identified that convey a risk for psychiatric diseases in addition to those genes which are linked to a therapeutic response to drug treatment. Knowledge of the latter forms the basis of pharmacogenomics which, hopefully, will eventually lead to the development of specific treatments for the individual patient.
The potential value of pharmacogenomics can be illustrated by two examples involving the response of individual patients to antidepressants. In this approach, the potential importance of the cDNA microarray technique for identifying changes in thousands of individual genes that are expressed in the mouse brain is now widely accepted. Experimental studies have indicated that different antidepressants exert distinct effects on gene expression in the mouse brain, these differences becoming more marked as the duration of the treatment increased. Such findings may eventually lead to an individualized treatment strategy for depressed patients based upon their cDNA analysis.
At the practical clinical level, individual differences in the pharmaco-kinetic characteristics of antidepressant drugs have been more successful. It is well established that the enzymatic activity of different allelic forms of the cytochrome P450 oxidase system in the liver is particularly important in the metabolism of many psychotropic and non-psychotropic drugs (see pp. 91-94). Of the major forms of cytochrome P450 in man, the 2D6 isozyme is particularly important in the metabolism of antidepressants and a potential cause of drug interactions. Three of the five commonly available SSRI antidepressants (fluoxetine, paroxetine and sertraline) undergo autoinhibition of this isozyme and can therefore increase the tissue concentration of a more toxic drug (for example, an antiarrhythmic or beta-blocker) should it be given concurrently.
Over 50 allelic variants of the cytochrome P450 2D6 gene have been identified, including individuals who lack the gene and others who have multiple copies of the gene. This means that an individual (the functional genotype) can either be normal, a slow or an ultra-fast metabolizer of a drug that passes through the 2D6 pathway in the liver. Slow metabolizers will therefore be at an increased risk for adverse effects while the rapid metabolizers will have little benefit from the normal doses. Thus genotyping the enzymes that metabolize the commonly used psychotropic drugs could help to optimize the response, and to indicate the potential for adverse drug effects, of the individual patient.
A new term has recently been introduced to cover the application of pharmacogenomics to the design of drugs for the individual patient, namely theranostics (from therapeutics+diagnostics). This approach involves creating tests that can identify which patients are most suited to a particular therapy and also to provide information on how effective this drug is in optimizing the treatment. Theranostics is said to adopt a broad dynamic and integrated approach to therapeutics which may be of practical relevance in differentiating diseases which are closely associated diagnostically (for example, Alzheimer's disease and Lewy body dementia) by applying a combination of immunoassays that enhance the differential diagnosis. Several biotechnological companies now specialize in designing immunoassays for application to infectious diseases such as hepatitis by genotyping the hepatitis C virus for example. There are six genotypes of the virus known: genotype 1 is more resistant to standard therapy (requiring at least one year of continuous therapy) whereas the other genotypes usually respond to treatment within 6 months. Clearly a knowledge of which viral genotype is present is important in determining the duration of treatment in the individual patient and hopefully it will soon be possible to extend such approaches to the drug treatment of central nervous system disorders.
Applying pharmacogenomics to the pharmacodynamic aspects of psychopharmacology is still at a very early stage of development, largely because so little is known of the psychopathological basis of the major psychiatric disorders or of the mechanisms whereby psychotropic drugs work. In depression, for example, it is widely assumed that the inhibition of the serotonin transporter on the neuronal membrane is ultimately responsible for the enhanced serotonin function caused by the SSRI antidepressants. The serotonin transporter is structurally complex. The promoter region of the transporter, to which serotonin is linked before it is transported back into the neuron following its release into the synaptic cleft, exists in several polymorphic forms which are broadly categorized into the long and short forms. It is known that when the polymorphic form occurs in which an additional 44 pairs of nucleotide bases are inserted, there is a higher transcription rate and a greater degree of binding of serotonin to the promoter region. The practical importance of this finding is that depressed patients with the long form of the transporter show a better response to SSRIs than those with the short form. In bipolar patients, there is an indication that the short form of the promoter is more likely to result in the precipitation of a manic episode if given an SSRI during the depressive phase of the disorder. There is also some evidence that the short and long forms of the transporter may be correlated with the frequency of extrapyramidal side effects and akathisia, which is sometimes caused by SSRIs.
There are two caveats that should be taken into account with regard to the application of pharmacogenomics. Drug response is as complex as the underlying genetic basis of the disease due not only to the genotypic variation taking place at mostly unknown chromosomal loci, but also from variations in gene expression, post-translational modification of proteins, pharmacokinetic features of the drugs, the effect of diet, drug interactions, etc. One would therefore anticipate that the effects of individual genes on the drug response are relatively slight. Thus it has been shown in studies of pharmacogenetic markers that they only confer a twofold increased likelihood of predicting drug response. However, the widespread application of microarray technology, whereby information on thousands of genes can be determined simultaneously, may help to overcome the limitations of the candidate gene approach, the method which until now has been used to obtain information on a few genes presumed to be involved in the underlying pathology of a disease or its response to drug treatment.
Another aspect requiring attention concerns the statistical evaluation of the results. For example, recently it has been shown that in a study of asthma one genotype had a 100% positive predictive value for non-response to a drug. However, because the susceptibility genotype only occurs in less than 9% of patients, in practice less than 10% of the non-response to treatment can be attributed to this abnormal genotype. In this case, it has been calculated that avoidance of the drug as a result of pharmacogenomic profiling would only improve its efficacy from 46% to 51%. Thus the reliance on candidate gene variation, which ranges from 2% to 7%, is currently not in the range for practical application.
In CONCLUSION, molecular genetics is providing important tools that enable the physiological role of specific receptors and enzymes to be elucidated. In situ hybridization is a powerful technique for locating receptors in specific brain regions and in studying the influence of drug treatment on these receptors. The accuracy, specificity and sensitivity of such a technique is substantially greater than any other available technique. Transgenic mice and ''knock-out'' mice are also providing valuable models of human disease that have not been obtained by other methods. With regard to psychiatric illnesses, molecular genetic techniques are being used in human genome screening which are designed to locate those genes that may be responsible for bipolar disorder and schizophrenia. By collecting cell lines from family pedigrees, it may be possible to determine the genes that contribute to alcoholism and Alzheimer's disease in addition to those involved in schizophrenia and the affective disorders. This may eventually lead to the identification of new methods for the pharmacotherapy of such conditions.
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Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.


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Solei Renew (Alien Dawg)
Rediscover that cozy feeling of getting tucked in and get tomorrow-ready. Bright green hues with a spicy citrus aroma, Solei Renew is perfectly flowered, sun-grown to the highest quality in an eco-friendly environment and harvested at just the right moment.
Product Attributes
- THC Content: 13 - 20%
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- Terpenes: Limonene (Citrus), Caryophyllene (Hoppy), Myrcene (Earthy/Musky)
- Licensed Producer: Aphria


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Hoffman Leaving Ad Sales Post at NBC After 26 Years
Jim Hoffman, executive VP for network entertainment sales and marketing at NBCUniversal, is leaving the company after 26 years.
No replacement has been named.
In an internal memo, NBCU Ad Sales president Linda Yaccarino told staffers that Hoffman had decided to leave at the end of next month.
"As many of you know, Jim has been a champion of the network, its programming and talent. He nurtured creative partnerships with, and created tremendous value for, our clients on behalf of the NBCUniversal Entertainment, Sports and News groups over the years. And, he has been a part of the best broadcast sales team in the industry for more than a decade," Yaccarino said in the memo. "We have watched him represent our company with dedication and class, and his contributions to the team have been countless."


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The 10th House
March 1, 2016
Be careful you don't miss
Our next traveller: his small
Stature and humble dress
Might fool some, but not us.
Dirty plough over his shoulder,
This one is clothed in the meek
Make of one who knows just
How simple life ought to be.
His horns protrude out of
Curly chocolate locks, and
Upon his head a hat of straw;
Good tilled earth is his home.
None left know much about him,
But all who know his name smile.
Mister Capricorn
January 18, 2011
Every January it's the same thing;
An annual event for a perennial struggle.
I always wish, quietly, that I could
Look back and watch each of my birthdays,
In sequential order, just to see each year
Within a single batted eyelash.
Each memory sticks like a cheap t-shirt
On a muggy summer day. I am soaked in it.
Now, as I enter a world where I give
All of myself to students and paper clips
Are treated like currency, I strain my eyes
To see all of my future birthdays
Stretched out ahead of me, like an
Ash-grey boardwalk. A million lives,
Running parallel to my own, rushing
Wildly like a river full of salmon.
If nothing else, I would wish my
Future self a very happy birthday.


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Volunteer Opportunities
NAMIWalks 2019
Join us to learn about volunteering for the 2019 NAMIWalks Palm Beach County! We need your help to fight stigma and promote awareness that recovery is possible. There are various day-of volunteer needs including: Set Up, Check In, Registration, Photography, Refreshments, Finish Line Cheer Squad and Clean Up Crew.
Thursday, October 24
Lake Worth Office
1520 10th Avenue North
Lake Worth, FL
Volunteer for NAMIWalks Palm Beach County 2019!
Saturday, November 2, 2019 at John Prince Park in Lake Worth, FL.
NAMIWalks brings together individuals, families, and businesses to help raise funds, fight stigma, and promote awareness that recovery is possible. NAMIWalks' public display of support for people affected by mental health conditions is one important way that we are changing how Americans view mental illness. Please join our efforts today by signing up on the NAMIWalks Website.
Volunteers are needed for:
- Walk Committee
- Team Coordinators
- Volunteer Coordinators
- Vendor Coordinator
- Public Relation Coordinators
- Sponsorship Volunteers / In-Kind Donations
- Walk Day
Walk Day Volunteers:
- Set Up: Early Morning
- Check In
- Registration
- Photography
- Refreshments
- Finish Line Cheer Squad
- More opportunities TBA
- Clean Up Crew
To volunteer or for more information, please contact Ryan Yule, Administrative Coordinator
at (561) 588-3477 or firstname.lastname@example.com


text: Prins van Oranje offers winterstorage as well. Our large (3.000 m2) insulated and heated pilot is suitable for more than 100 boats. Our certified professionals carry out all lifting- and transport activities for you. We offer winter maintenance as well, meaning we bring your boat in top condition and make sure it will be ready to sail before start of the new sailing season.


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Here are Some of the Things You Should Do After an Accident
So you've experienced a car crash. It happened abruptly, and now your mind is rushing, and also you are not sure how to proceed. These specific things happen, and no one expects them, but remain consider and calm things one step at a time. Everything is likely to be okay if you follow several steps that are easy.
Never leave a car crash's scene. The worries and shock of getting right into a car wreck may feel like more than it is possible to handle, however it is not. Maintain concentrated and relaxed and not abandon the vehicle crash's picture. When the concern and fear overcome you, and you flee the picture, you've dedicated a crime significantly worse than creating an automobile accident (that might not need to be your problem!). Being convicted of a hit-and-run is considerably, far worse, and can land you in jail to be charged of producing a vehicle accident as opposed to discomfort.
You will need to get information from the people concerned. Get their insurance data, their driver's certificate numbers, telephone, and handles. Obtain a list of witnesses who noticed the vehicle accident whatsoever, of witnesses.
Make sure to find medical attention if you have been hurt. Signs might reveal themselves hours and sometimes even days, even when you don't believe you have been hurt soon after the vehicle accident. It is best to determine a health care provider immediately so you could be examined. No signs may be given by some incidents, but might be deadly in times or a couple of hours. Find medical attention.
Create a police statement. A car crash is actually a critical matter that could affect your finances, your insurance, and your health. It is a great thought to help make the motor vehicle accident an incident of official record by having a police statement. Call law enforcement to come quickly to the picture of the automobile crash. Visit the neighborhood police stop if in your town law enforcement just react to incidents that need an ambulance and document a study. Make sure to document law enforcement report's number.
Take pictures of the vehicle crash's picture. Many people bring a camera within their glove pocket because of this. Take pictures of any damages that's been done and of the automobiles concerned. Take images of any incidents also, like cuts. Ultimately, protect the state of the car so that insurance agents could inspect it before it truly is restored. the precise injury is better, although it's much better than nothing in case a picture is all you've got.
You are able to start your entire day when you obtain the necessary data to produce a claim. You will need to call the insurance carrier to offer the info to them.
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text: CITY PLAN is presently working in these 5 states, including Florida, Pennsylvania, South Carolina and Oklahoma. We also have a location in Liberia, Africa. This directory will aid in finding CITY PLAN resources. Please check back often, as new locations and services will be added soon. Please click here to visit CITYPLAN.TV


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Aaron Hall, president of Texas Houston South Mission, recently posted an update on Facebook, sharing how missionaries are serving others during the fallout of Hurricane Harvey.
"For those serving in downtown Houston, and where roads are clear safe, they had the opportunity to serve at the George R. Brown Convention Center where there are currently 10,000 evacuees. The city has a great need for volunteers and the missionaries are so excited to be part of the early relief efforts," he writes.
For missionaries in other areas of Houston, President Hall says they "are having the opportunity to see first hand the devastation and are equally anxious to help," but that missionary safety is top priority.
Then, President Hall shared a powerful message about finding the Savior's life, even in the midst of destruction and suffering:
"A beautiful tender mercy today as the storm moves on... At 5:30 the sun beamed brightly through the clouds after five days of rain and gloom. In that moment it was as if heaven itself was shining down on us (I took the attached picture to remember the moment). It was odd to think that just a week earlier the nation was captivated by a total solar eclipse and the darkening of the day. I have never been more grateful to see the sun as I was today and it lifted our souls. So it is true with the Son God. He will brighten our souls on any darkened day as we look to Him in faith.
"Thanks for your continued faith and prayers, much work ahead, we can't wait to bless and serve."


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Keeping her out of the flower garden is a losing battle so I have come to embrace the fact that I have a garden "helper".
Now only if I could get her to do some weeding!
Do you have a garden "helper" like Miley?
Oh, we LOVE your pink flamingos! Being from Florida, we see those birds in yards all the time and they are perfect for your garden.ReplyDelete
That is so cute! You should plant some strawberries, so she can have snack while helping! :)ReplyDelete
Miley clearly has a green paw! And if you're successful at teaching her to weed, Mommy's sending us to your house for lessons.:)ReplyDelete
She fits right in. I'm always trying to stop ours from weeding some of what they get into not so healthy.ReplyDelete


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Determining the Best Lawn Care Services
The ability of the lawn owner to get the desired appearance of the lawn will be determined by the lawn service that the owner will employ. Regular lawn care services are important to help maintain the health of the lawn. The presence of the lawn increases the value of the property within the area. Commercial lawns help to attract customers to the business thus increased profits for the owner. The decision for a property owner to keep a lawn within their compound might be as a result of the beauty effect they have seen from other properties.
The lawn care services requires trained professionals to be able to maintain the best quality of a lawn. The owner of the lawn should consult from their friends about the available lawn companies to be able to identify a company with the right professionals. The trained professionals have the capability of maintaining an attractive lawn as they have the skills to determine the kind of action that needed to be taken to maintain the best condition on the lawn. The lawn care companies should ensure that they carry out internal training for their employees to ensure that they are aware of the procedures involved in every action of the lawn care services.
The efforts of the lawn owner to identify a company with the best professional designers will enable them to have the best design for their lawn. The lawn owner should request to see the various lawn designs that the company have been able to deliver to their clients. The lawn owner should identify other clients that the lawn care company has been serving to inquire about the quality of service they can expect from the company.
The lawn owners can be guaranteed of quality service for their lawn by getting a company with experienced professional. Most lawn care companies that have been in operation for a long time have the most experienced workers and thus the need for the lawn owners to consider their services The longtime period of service in the lawn care services equips the professionals with advanced skills to offer perfect services for a lawn.
The landscaping activities on a lawn require the use of special equipment. The lawn care equipment is usually expensive to acquire. The lawn owner should thus identify a financially stable lawn care company due to the ability to have the right equipment. The owner of the lawn should identify a lawn care company with the best customer services since the will be in constant communication with the lawn care professionals. The ability of the lawn owner to compare lawn care charges from different service providers will enable the individual to pay low for the services.
Gardeners – Getting Started & Next Steps