Archive for March, 2008

The Kitchen

Don’t allow food to spoil, but if it does, discard it immediately, then wash and dry receptacles thoroughly. Use a fan or open the windows to remove excess steam when cooking. Look out for mold on cutting boards and sponges, in sink and disposal stoppers, refrigerator gaskets and drip pans, washing machines, garbage containers, and places where fresh food is stored. Watch for dust and mildew atop, behind, and under sinks, stoves, refrigerators, and other hard-to-reach places.

All Rooms

Bare is beautiful. The fewer objects lying around, the better. Books, magazines, light fixtures, shelves of knickknacks, TV sets, even clothes collect dust. Move small objects to drawers and cabinets and keep the furniture 3 to 5 inches from the wall, so you can vacuum behind them. Store all garments in clean closets with closed doors. If you must dust the room yourself, use damp rather than dry dusting, and wear a disposable face mask. To get to hard-to-reach places atop refrigerators or behind headboards, wrap a moist rag around a pole or yardstick. Painted walls are preferable to wallpaper because the flour in wallpaper paste has a high content of mold spores. So do fabric hangings and tapestries. If practical, replace upholstered chairs and sofas with. canvas, metal, plastic, or simple wood furniture. Decorative pillows and stuffed animals attract dust. One mother tells her daughter she’s taking her teddy bear for a ride, then pops him into the dryer for a half-hour spin at high heat. An alternative is to put Teddy in an airtight plastic bag and place him in the freezer for two to three days. It takes that long for the cold temperature to kill the mites, although it doesn’t remove their debris. A third possibility is to cut open the toy, replace the stuffing with old nylon stockings or polyester fill, and sew up the seam.

The Floor

New carpet loses its strong chemical odor over time, but as it ages, it becomes a haven for microorganisms-dust mites, mold spores, animal dander, and the like. A University of Virginia study found that carpets accumulate allergens at one hundred times the rate of a bare floor. If possible, carpets should be replaced. The ideal nonallergenic floor is a hardwood, tile, or vinyl surface that can be cleaned with a wet mop-twice a week, at least-and covered with small washable rugs. Don’t use brooms; they stir up too much dust.The best vacuum to buy is a tank-type with strong suction and an extension on the hose so that the canister can sit outside the room during vacuuming. Dust-filtering bags are available from allergy supply companies for $ 6 to $ 10 for a set of five. Leave the task of changing them to someone else. Many new and more expensive ($ 400 and up ) vacuum cleaners come equipped with HEPA ( high efficiency particulate arresting ) filters specially designed to trap fine particles as small as . 3 microns. ( A micron is ”/, mw of a millimeter .) Consumer Reports studied vacuum cleaners in 1997 and reported : ” If someone in your family has asthma or allergies, consider using one of the high-performing models as your regular vacuum cleaner. Many airborne allergens-notably pollens-are much larger than the particle sizes we tested, so cleaners that performed well on our tests will also trap the larger particles effectively. But don’t expect a high-filtration vacuum cleaner to substitute for longer-lasting environmental controls, such as removing carpeting or encasing bedding in mite-proof covers .”

The Windows

Roll-down shades and. unlined washable curtains are preferable to dust-catching blinds and draperies. Keep windows closed during pollen season and at peak pollen hours, usually 5 A. M. to 10 A. M. Use central or room air conditioning switched to the ” recycle ” or ” recirculate ” setting. Air conditioners are great pollen traps, so clean them and change filters scrupulously. If possible, avoid heavy draperies and Venetian blinds in favor of light cotton or synthetic curtains that can be washed regularly. Shades are fine if dusted at least once a week.

The Bathroom

Prevent molds from growing by wiping down shower curtains, walls, tub, toilet, tile, and all damp areas with a mixture of cup of bleach to 1 gallon of water ( or one part bleach to ten parts water ) at least once a month. Four times a year use Zephiran ( benzalkonium chloride ), 1 fluid ounce to 1 gallon of water, to further inhibit mold growth. Allow plenty of ventilation, and let surfaces air-dry-or better yet, install an exhaust fan. Keep as few toxic cleaning products and pesticides in the kitchen as possible. ( See chapter 17 for nontoxic substitutes .)

Outdoor allergens are almost impossible to control. In your home, however, you rule the atmosphere. The cleaner the air you breathe, and the more dust, pollens, molds, and dander you can banish from your indoor environment, the better your chances of getting good results from pills, sprays, or shots. Your eventual goal is to live and work in settings so free of irritants and allergens that you won’t need any medication.

CLEANING HOUSE

Dust reduction is your main priority. Begin in the bedroom, be- cause it ‘ s where adults spend one-third of their time and children spend half their time. It’s also home to the greatest number of dust mites. Once you’ve done the bedroom, apply the same principles to the rest of the house, including closets.

The Bed

Not a pretty picture, but do you realize that thousands of tiny dust mites share your bed and bedding every night? If you weren’t so hospitable, they’d starve-and that’s exactly what you want to happen. The little beasties can’ t crawl through plastic, so encase your mattress and box spring in airtight zippered covers, then apply tape over the zippers. Mattresses not only draw mites ; many contain allergenic materials such as horsehair. Allergy specialty stores like Gazoontite ( see appendix D ) sell protective mattress covers, not only in heavy-duty vinyl but also in machine-washable blends of cotton and polyester. Some are fortified with an antibacterial agent to protect against molds. The bed should, be made of wood or metal. Try to avoid wool, down, feather, kapok, and ( moldattracting ) foam rubber products. Polyester, linens, or cottons are fine for most people, although one 1999 British study compared dust mite levels in feather and synthetic pillows and found higher levels of dust mite allergens in the synthetic pillows. Studies show that the average year-old pillow houses no fewer than 250, 000 mites, and that up to 20 percent of a pillow’ s weight can come from mites and their waste. Perhaps the answer is to buy inexpensive new pillows and replace them annually-or, as one enterprising mother does, make your own pillows out of soft white towels. Then, once a week, toss the whole thing into the washer. Blankets, sheets, and cotton or polyester pillowcases should be machine-washed in very hot water ( 140 degrees Fahrenheit ) every seven to fourteen days. Eliminate such dust collectors as quilts and comforters, and in general, keep your bed simple. If you can’ t bear to part with Grandma’ s quilt or your rose-patterned comforter, wash them first, then dry them in the dryer. An hour of dry heat dramatically reduces the dust mite population. Canopies, padded headboards, bunk beds, and ruffles are far too hospitable to the critters. Don’ t overlook your clothes, especially outerwear such as jackets, wool caps, mittens, and sweaters. Wash in cold water, then dry for fifteen minutes at a high temperature or stash in the freezer overnight. Incidentally, dust mites don’ t much care for mothball fumes. A Connecticut study found that mothballs, mothball crystals, and mothball oil packets destroy dust mite eggs. The bad news is that mothball vapors can be irritating to humans, especially asthmatics or anyone sensitive to chemicals. The Journal of Allergy and Clinical Inimunologil recently reported that Australian researchers added eucalyptus oil to laundry and found it killed 95 percent of mites that survived the high temperatures.

PDE5 is a dimeric enzyme that is composed of two identical 100 kD proteins. There are four known isoforms of PDE5 ( PDE5A 1-4 ) ACC . No : NM _ 03343I : these isoforms are products of a single gene and are formed by alternative splicing of mRNA . The enzymatic characteris- tics of the PDE5A1-3 appear to be quite similar although there may be some selectivity in their tissue distributions ; PDE5A3 is largely expressed in smooth muscle. The enzymatic properties of PDE5A4 have not been character- ized . Each of the monomers in PDE5 is a chimeric protein that contains two major functional domains that are approximately equal in size , i . e ., a catalytic domain ( C domain ) located in the more C-terminal portion of the protein and a regulatory domain ( R domain ) located in the more N-terminal portion. The single catalytic site located in the C domain is the target for sildenafil. The R domain of PDE5 contains allosteric cGMP-binding sites that contribute importantly to regulation of enzyme functions and to potency of these PDE5 inhibitors . However , the allosteric cGMP-binding sites in PDE5 are evolutionarily and biochemically distinct from that of the catalytic site . These sites are highly specific for cGMP : and do not interact with sildenafil. The catalytic site binds cGMP in a shallow pocket along the sur- face of the enzyme . When cGMP occupies this site , the cyclic phosphate bond of cGMP is brought into proximity with the catalytic machinery of the enzyme , which involves an array of amino acids and divalent cations including Zn2 +. This arrangement provides for the rapid hydrolysis of the cyclic phosphate bond of cGMP to form 5 ‘ -GMP , which has low affinity for the enzyme and rapidly dissociates from PDE5 . 5 ‘ -GMP is inactive in the cellular cGMP-signaling pathway . Other cellular phosphohydrolases do not hydrolyze the novel cyclic phosphate bond of eGMP or cAMP . Because the structure of sildenafil resembles that of eGMP , it can occupy the PDE5 catalytic site , thus blocking access to eGMP . In addition , sildenafil is stable and is not inactivated by the catalytic machinery ; nor is it metabolized significantly in the smooth muscle cell . For these reasons , occupation of the PDE5 catalytic site by sildenafil competitively inhibits eGMP breakdown since eGMP cannot gain access to the catalytic machinery . In the face of ongoing synthesis of eGMP in any tissue containing PDE5 , this will cause eGMP to accumulate and to increase cGMP signaling through PKG . In the penile corpora cavernosa , this contributes to improved erectile function . Although the C domain of PDE5 is the direct target of PDE5 inhibitors, functions of the R domain enhance the PDE5 inhibitor actions on the enzyme . Allosteric cGMP-binding is provided by sites in the R domain ; whether one or two eGMP molecules are bound per subunit is still unclear . In addition , there is a single consensus phosphorylation site for PKG or PKA near the N-terminus . Phosphorylation of this site activates PDE5 catalytic function and thereby provides for negative feedback regulation of cGMP levels. Phosphorylation of this serine is tightly controlled by cGMP levels since occupation of the PDE5 allosteric cGMP-binding sites is required for phosphorylation to occur , and the site is preferentially phosphorylated by PKG compared to PKA . Therefore , it is likely that the site is only phosphorylated when cGMP is elevated in the cell . When cGMP binds to the allosteric sites , cGMP is not degraded as it is in the catalytic site , but PDE5 enzyme functions are altered . Cyclic GMP binding to the allosteric sites in the R domain pro- duces a conformational change that exposes the serine allowing it to be rapid- ly phosphorylated , thereby increasing PDE5 catalytic activity. Cyclic GMP occupation of the allosteric sites also increases the affinity of the catalytic site for cGMP , thereby further activating PDE5 catalytic site func- tions. However , in the presence of a PDE5 inhibitor and ongoing syn- thesis of cGMP , cellular cGMP is elevated , which fosters increased binding of cGMP to the allosteric sites and phosphorylation of the serine by activated PKG ; as a result , the affinity with which PDE5 inhibitors bind at the catalytic site is increased . Therefore , due to its molecular mechanism , the potency of sildenafil is actually greater than would occur in the absence of the R domain . This property of the enzyme translates into greater clinical efficacy and poten- cy of sildenafil and other PDE5 inhibitors . Following ingestion of a PDE5 inhibitor tablet , any elevation of cGMP in smooth muscle cells should increase the avidity with which the PDE5 catalytic site binds that inhibitor . That is , the PDE5 inhibitor , by fostering increased binding of cGMP to PDE5 allosteric sites , stimulates its own efficacy and potency.

Sildenafil is a competitive and reversible inhibitor of cGMP hydrolysis by the catalytic site of PDE5 . Sildenafil is an analog of cGMP , the PDE5 substrate , but PDE5 has - 1000-fold higher affinity for sildenafil than for cGMP. The purine ring of cGMP is mimicked by similar components in sildenafil , and this undoubtedly provides in part for the specificity of the com- pound for the PDE5 catalytic site. However , the novel components of the sildenafil structure provide for the higher affinity , and these additional ele- ments in the sildenafil structure most likely exploit interactions in and around the PDE5 catalytic site that are not utilized in interacting with cGMP . Furthermore , these distinctive structural components most likely contribute to the specificity of the compound for the PDE5 catalytic site since the structure cannot be accommodated in other cGMP-binding sites such as those found in PKG and cGMP-gated cation channels , in the catalytic sites of other PDEs , or in the allosteric cGMP-binding sites of PDE5. The characteristics of the novel interactions between sildenafil and the catalytic site of PDE5 are empha- sized by the fact that the potency of sildenafil can be significantly altered by minor changes in its molecular structure . Although the molecular differences in sildenafil and vardenafil are apparently modest , vardenafil is -10-40 times more potent in inhibiting PDE5. Among several possibilities , this could be due to the different positions of nitrogen atoms in the imidazotriazinone ring of the two compounds , which might engender differences in electron dis- tribution .