How to Prevent Arthritis

 
Arthritis pain and stiffness set in when the cartilage  the rubbery cushion in the joints that absorbs shock for the bones and allows them to glide smoothly when we move  wears away. When there isn’t enough cartilage left in the joint to protect the bones from damaging each other, we feel it. And while over 46 million Americans are living with arthritis, about 61 percent of them, or 28 million, are women.
Why are women more commonly affected by arthritis? One reason may be the physical differences between the sexes  for example, women have less knee cartilage than men. It's no wonder that according to a recent report, knee replacement surgeries more than tripled in women between ages 45 and 64 over the past decade. Women are also at greater risk for the autoimmune condition rheumatoid arthritis than men, which experts think may be due to hormonal differences, among other factors. Finally, women may also experience a greater emotional burden from arthritis than men. A 2011 survey conducted by the supplement manufacturer Flexicin International found that 78 percent of women with arthritis feel that they receive very little support from family and friends, compared with 66 percent of men.

Fight Back Against Arthritis

So what can you do? The good news is that there are risk factors for osteoarthritis that women can target for arthritis prevention. Start with these important steps.

18 Ways to Boost Your Wi-Fi Signal and Speed it up

 We’ve all been there: You're watching the latest season of Orange is the New Black on Netflix when, all of a sudden, the video jerks to a stop and the endless buffering begins. It's frustrating when your network slows down (or shuts down completely), but there are a few tricks you can use boost your Wi-Fi signal. Here are a few of them.

1. Do not hide your router

Most people hide their routers because they’re unsightly or in the way, but placing a router in a closet or in a cabinet is a one-way ticket to slow Wi-Fi: Walls and doors can degrade and absorb signal strength. Find a central location in your home and put your router on a table or bookshelf. Because some routers are designed to project a Wi-Fi signal slightly downward, keeping it higher off the ground will evenly distribute a Wi-Fi signal throughout your home.

2. Stay away from appliances and metal objects

Microwaves, cordless telephones, flourescent lights, and even other routers in your neighbor’s home or apartment may interfere with your Wi-Fi signal. To reduce interference, place your router away from household appliances and set it to a different wireless channel and frequency. Using online tools, Acrylic Wi-Fi for Windows and AirGrab Wi-Fi Radar for Mac, for example, can help you find the right wireless channel with the least amount of interference. If you want an easier fix, most routers have an automatic option to find the best channel for your location.
You should also avoid placing your router near metal objects, which can absorb signal strength.

How To Lock Down Wireless Network

To prevent your wireless network form other hackers, you need to LOCK IT DOWN. If you operate a wireless network for your home or business, it's important to protect it against opportunistic hackers seeking to steal your data or hijack your Wi-Fi for their own nefarious purposes. We spoke to Steven Andrés, CTO of security consulting firm Special Ops Security, to learn about the best ways to lock down your Wi-Fi. To get started, you'll need to log in to your router's administrative console by typing the router's IP address into your Web browser's address bar. Most routers use a common address like 192.168.1.1, but alternatives like 192.168.0.1 and 192.168.2.1 are also common. Check the manual that came with your router to determine the correct IP address; if you've lost your manual, you can usually find the appropriate IP address on the manufacturer's website.

Change Your Passwords

The first step in securing your network is simple: Change your passwords! Default router passwords like "admin" are seductively simple to remember, but that means they're equally simple for a hacker to guess; there's even a public database containing default login credentials for more than 450 networking equipment vendors. Though no password is foolproof, you can build a better password by combining numbers and letters into a complex and unique string. Remember to change both your Wi-Fi password (the string that guests enter to access your network) and your router administrator password (the one you enter to log in to the administration console the two may sometimes be the same). Andrés suggests that you change your passwords to something unique no pet names and then write them down on a piece of paper and tape them to your router for safekeeping.

How to Change WiFi Network’s Password and Name step by step

Your Wi-Fi router comes with a default network name and password, and both are often printed on the router itself. But you can change the name and password to anything you want in just a few clicks.
Changing your default network name gives you a chance to use something more personalized than “NETGEAR30” or “Linksys.”  I recommend you to use a password that’s easier to remember.

Find Your Router’s IP Address

 This setting is controlled on your wireless router, so you’ll need to change it on your router.
Typically, this will involve accessing the router’s web interface in a web browser and changing it there. But this depends on your router. For example, if you have an Apple Airport router, you can use the “Airport Utility” on your Mac to change its settings. Some router manufacturers offer smartphone apps for changing settings, while some more expensive routers are even beginning to include built-in touchscreens for this.
But all this doesn’t really matter for most people. Typically, you’ll need to access the web interface. You could look up instructions specific to your model of router online, but the below instructions will work for the vast majority of routers.
(You should probably do this from a computer. Many routers don’t have a mobile-optimized website that will work well on your smartphone.)
On a Windows PC, the quickest way to find this information is in the Command Prompt. To open it, press Windows Key + R, type “cmd” without the quotes, and press Enter.



Type “ipconfig” without the quotes into the Command Prompt window and press Enter. You’ll see the router’s IP address displayed to the right of “Default Gateway” under the network connection you’re currently using.
This works on Windows 7, 8, 8.1, 10, and even older versions of Windows.



On a Mac, click the Apple menu and select “System Preferences”. Click the “Network” icon, select your Wi-Fi or wired Ethernet conneciton, and click “Advanced”.



Click over to the “TCP/IP” tab and look for the router’s address to the right of “Router”.

Access the Web Interface

Take that IP address you found earlier, type it into your web browser’s address bar, and press Enter.



You’ll be asked to enter the router’s username and password to log in. If you’ve changed the username and password to custom ones, enter your custom login information.
If you haven’t, you’ll need to use the default login information. Often, the default password is either “admin” or just blank. On some routers, you may need to enter “admin” as the username and a blank password, “admin” as both the username and password, or “admin” as just the password with a blank username.
To find out the username and password for your router, perform a web search for “default password” and the name of your model of router, or check your router’s documentation. This page offers a list of default usernames and passwords for many different routers.
If you’ve set a custom password but can’t remember it, you’ll need to reset your router to its default settings.

Change the Wi-Fi Network Name and Password

After logging in, look for the Wi-Fi settings. Depending on your router, these may be right up-front on the first page you see, or they may be buried in a section named something like “Wi-Fi”, “Wireless”, or “Wireless Networks”. Click around and you should find it.
You may see a field named either “SSID” or “Network name”. These are the same thing — the name of your wireless network.
The “password” and “passphrase” fields are also the same. It’s recommended to choose a fairly long wireless password, and you may want to use a phrase — a series of words — rather than a single word. This field may also be named the wireless “key,” WPA-PSK key, or something similar.



Once you’ve entered your new Wi-Fi network name and passphrase, you’ll need to click “Apply”, “Save”, or a similarly named button to save your settings.
If you’re connected to your router’s web interface over Wi-Fi, your device will disconnect as the router shuts down its old Wi-Fi network and brings up a new one. On every device you use, you’ll need to open the Wi-Fi settings, choose your new Wi-Fi network name, and enter its new passphrase to reconnect. All devices currently on the network will need the new details before they can connect again.

how to make good relationship with others

Do a Google search on how to get your best body and you’ll be inundated with pages of training tips. For those who want to take that same, proactive approach to creating your best relationship, I have your "exercise regimen" below:

1. Do the things you did the first year you were dating
 
As the months and years roll on, we tend to slink into our proverbial sweatpants and get lazy in our relationship. We lose our patience, gentleness, thoughtfulness, understanding and the general effort we once made toward our mate. Think back to the first year of your relationship and write down all the things you used to do for your partner. Now start doing them again.

2. Ask for what you want
 
Over time, we assume that our partner knows us so well that we don’t need to ask for what we want. What happens when we make this assumption? Expectations are set and just as quickly, they get deflated. Those unmet expectations can leave us questioning the viability of our partnership and connection. Keep in mind that “asking for what you want” extends to everything from emotional to sexual wants.

3. Become an expert on your partner
 
Think about who your mate really is and what excites him or her (both physically and emotionally). We can become consumed by what WE THINK he/she wants, as opposed to tuning in to what truly resonates with the other person. Remember that if it’s important to your partner, it doesn’t have to make sense to you. You just have to do it.

4. Don't ask "how was your day" 
 
At the end of a long day, we tend to mentally check out of our lives and consequently, our relationship. We rely on the standard question, “How was your day?” Generally, that boring question will yield a boring answer such as, “Fine, how was yours?” This does nothing to improve your connection and instead, can actually damage it because you're losing the opportunity to regularly connect in a small way.
Instead, try asking things like, “What made you smile today?” or “What was the most challenging part of your day?” You’ll be amazed at the answers you’ll get, with the added benefit of gaining greater insight into your significant other.

5. Create a weekly ritual to check in with one another
 
It can be short or long but it begins with asking each other what worked and didn’t work about the previous week and what can be done to improve things this coming week. Additionally, use this opportunity to get on the same page with your schedules, plan a date night and talk about what you would like to see happen in the coming days, weeks, and months in your relationship. Without an intentional appointment to do a temperature check, unmet needs and resentments can build.

6. Keep it sexy
 
What might change in your relationship if both you and your partner committed to increasing the behaviors you each find sexy and limiting those that aren’t? Think about this in the broadest form. “Sexy” can certainly refer to bedroom preferences, but it also represents what excites us about our mate in our day-to-day lives. Do you find it sexy if he/she helps with the housework? Do you find it "unsexy" when he/she uses the restroom with the door wide open? Talk about what it specifically means to "keep it sexy" in your relationship. Be amazed, be humored, be inspired.

7. Get creative about the time you spend together
 
Break out of the “dinner and a movie” routine and watch how a little novelty can truly rejuvenate your relationship. On a budget and can’t go big? Jump on the internet to look for “cheap date ideas” and be blown away at the plethora of options. Can’t afford a sitter? Try swapping babysitting time with friends that have kids. It’s free and they will likely be thrilled to take your kids because they will get to take advantage when they drop their kids at your place.

8. Get it on
 
Unless you have committed to an asexual partnership, sex, sexual contact and touching (kissing, holding hands, cuddling etc.) are vital components of a romantic relationship. The frequency is of course, up to you and it's imperative that you discuss your ideas about it in order to prevent resentment. Rare are the moments when both partners are “in the mood” at the exact same second, but that doesn’t mean that you have to decline their advances. Remind yourself that you will almost always “get there” after the first few minutes and that an intimate interaction of any kind builds connection and elevates your mood and health. Bear in mind that you are never required to say “yes.” If you truly don’t feel it, the best thing you can do is to postpone. Just make sure that you initiate or accept within a reasonable amount of time thereafter.

9. Take a (mental) vacation, everyday
 
Life and work distractions can become paramount in our minds and that leaves little time or energy for our partner. Practice the art of “Wearing the Relationship Hat.” This means that (barring any emergencies or deadlines), we are fully present when we're with our mate. We truly hear what they are saying (instead of pretending to listen), we leave our distractions behind and we don’t pick them up again until the sun comes up and we walk out the door.
Some tips to improve communication
Sadly, we aren’t born with the innate ability to effectively communicate but it doesn’t mean that we can’t learn. Use the following techniques to better navigate and limit the tension in your relationship:

10. Take "fight breaks" when you need them
 
Before you’ve hit the point of no return and as you see the stress beginning to escalate, one or both of you can call a break so that cooler heads can prevail. The crux of this tool lies in the fact that you must pick a specific time to revisit the conversation (I.e. 10 minutes from now, 2:00pm on Tuesday etc.) so that closure can be achieved.

11. Dig deep to unearth your true feelings
 
In most disagreements, we communicate from the “Top Layer,” which are the obvious emotions such as anger, annoyance and the like. Leading from this place can create confusion, defensiveness and ultimately distract from the real issue. Start communicating from the “Bottom Layer” (i.e. What feelings are really driving your reactions such as disappointment, rejection, loneliness, disrespect etc.).
This type of expression creates an instant sense of empathy because it requires honesty and vulnerability to share from this space. Tension will dissipate and from here, solutions can spring. Just be sure to use kind, non-reactive phrasing when expressing these bottom layer feelings, such as “I felt hurt by…” as a replacement for “You’re such a jerk” etc.

12. Seek to understand ... not agree
 
Easy in concept, difficult in application. Conversations quickly turn to arguments when we're invested in hearing our partner admit that we were right or when we are intent on changing his/her opinion. Choose to approach a conversation as an opportunity to understand your significant other’s perspective as opposed to waiting for them to concede. From this perspective, we have an interesting dialogue and prevent a blow out or lingering frustration.

13. Make your apology count
 
It’s well understood that apologizing is a good thing but it only makes a real impact when you mean it. Saying things like “I’m sorry you feel that way” or “I’m sorry you see it that way” are a waste of time and breath. Even if you don’t agree that your action was wrong, you will never successfully argue a feeling.
Accept that your mate feels hurt and from this place, a real apology can have a significant impact. When you love your partner and hurt them (intentionally or not) you can always legitimately apologize for the pain you caused regardless of your perspective on what you did or didn’t do.
You are now, officially armed with the comprehensive exercise routine to fully reshape your relationship. Trim the fat and build your hottest relationship for life!

8 Ways to Make Eyebrows Look Beautiful

Your brows frame your face and give it structure, so it's important to keep your t

iny arches on point at all times. Worried yours are a little wonky? Cosmopolitan.com asked makeup artist and brow wiz Cyndle Komarovski what makes your arches look off and how to make them pretty, pronto. You're welcome.

1. You're squaring off the front of your brows. Doing this too harshly can immediately make them look drawn on (aka fake). Instead, create shape by using tiny, hair-like strokes, regardless of whether you use a pencil, an angled brush topped with brow powder, or a brow mascara.

2. Your eyebrow's tail is too long

 Overextending the tail of your brows can create a droopy effect, drawing your face down. Your eyebrows naturally stop at a place that lifts your face up and out, which is what you want to maintain. To figure out where the tail of your brow needs to end, hold a brow pencil diagonally at your nostril and line it up with the side of your eye. Where the pencil hits your brow bone is where the end of your eyebrow should end (or can be extended to) without it looking unnatural.

3. You're exaggerating your eyebrow's arch

 Pointy arches can make you look surprised or angry even when you're not. So, if you weren't born with a high arch but want to create a subtle one, hold a brow pencil against your nostril and line it up diagonally with the center of your eye. That's exactly where any arch should go naturally.

Next, with a spoolie brush, like E.L.F. Cosmetics Essential Eyelash and Brow Wand, work your eyebrow hairs downward. With your brow product of choice (a pencil and a light touch might be your best bet!), ever so slightly alter your brow shape by creating a slight peak at the roots of the hairs at the top of your brows. Finally, brush your brow hairs back up with the spoolie brush so they fall into place and the arch looks natural.

4. You aren't shaping your brows

 Unruly brows are one thing (They're actually in right now!), but unshaped brows don't frame your face as well as well-groomed brows could. Don't have time to see a brow expert? Simply follow the shape of your brow (where the most hair is) and tweeze any strays that fall outside of that shape for perfect arches.

5. You have bald brow spots

 If you've fallen victim to over-plucking in the past, you're not alone. To conceal sparseness, fill in the spots with brow powder using an angled brush or you can opt for a pencil. Then, groom your brows into place with a brow mascara, like Maybelline New York Eye Studio Brow Drama Sculpting Brow Mascara.

6. You're using too much highlighter. Outlining your brows with a highlighter can put too much of a spotlight on your arches. Instead, opt for a concealer that's one shade lighter than your skin to brighten up your brow area. Try NudeStix Concealer Pencil.

7. You're over-filling your brows

  This can make you look like Groucho Marx's twin. The key to making your brows look darker but natural is not getting the formula you're using on your skin. If you have a bald spot you're trying to fill in, that's one thing, but if you're just trying to deepen your brow hair color, your best bet is a brow mascara that you can lightly swipe on for a more dramatic yet believable effect. Try L'Oréal Paris Brow Stylist Plumper Brow Gel Mascara.

8. You're doing a patchy job of filling in your brows

 If you feel like you only need to amp your arches up at the beginning of your brow, you still need to brush or apply whichever brow product you're using through to the ends. You can taper the amount off toward the tail so it's not as intense, but if you don't apply it to your entire brow, you'll end up with an uneven look, which no one wants.

How to install the latest version of Kaspersky antivirus 2016

Offline Installer for Kaspersky 2016 products (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016)

Compatible with Windows 10 | Windows 8.1 | Windows 8 | Windows 7 | Windows Vista | Windows XP.
Offline Installer doesn’t require network connection to install your new Kaspersky 2016 product, so you can install your new Kaspersky product while being offline.

Follow these steps to install your Kaspersky 2016 product.

NOTE: If your purchase covers more than 1 computer (for example, you purchased Kaspersky Internet Security 2016 for 3 PCs), it must be installed identically on all computers.

Step 1 - Read and Accept the the License Agreement

Read the License Agreement thoroughly and, if you agree with all of its terms, click the Accept button. The installation will then continue.

Step 2 - Install Process

The installation process can take some time. Wait for it to finish.

Once the installation is complete, the Wizard will automatically proceed to the next step.

Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) performs several checks during installation. Those checks may result in detection of the following problems:

Non-compliance of the operating system to the software requirements. During installation the Wizard checks the following conditions:

• Whether the operating system and the Service Packs meet the software requirements
• Whether all of the required applications are available
• Whether the amount of free disk space is enough for installation.

If any of the above-listed requirements is not met, a notification to that effect will be displayed on the screen.

Presence of incompatible applications on the computer - If any incompatible applications are detected, they are displayed in a list on the screen, and you will be prompted to remove them. Applications that Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) cannot remove automatically should be removed manually. When removing incompatible applications, you will need to reboot your operating system, after which installation of Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) will continue automatically.

Presence of malware on the computer - If any malicious applications that interfere with installation of Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) software are detected on the computer, the Setup Wizard prompts you to download a dedicated tool designed to neutralize infection and named Kaspersky Virus Removal Tool.

If you agree to install the utility, the Setup Wizard downloads it from the Kaspersky Lab servers, after which installation of the utility starts automatically. If the Wizard cannot download the utility, you will be prompted to download it on your own by clicking the link provided.

Step 3 - Completing Installation

At this step, the Wizard informs you of the completion of the application installation. To run Kaspersky 2014 immediately, make sure that the Run Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) check box is selected and click the Finish button.

In some cases, you may need to reboot your operating system to complete installation. If the Run Kaspersky 2016 check box is selected, the application will be run automatically after you reboot your operating system.

If you have cleared the Run Kaspersky 2016 (Kaspersky Antivirus 2016, Kaspersky Internet Security 2016 and Kaspersky Total Security 2016) check box before closing the Wizard, you will need to run the application manually.

Click the Finish button to close the Wizard.

Kaspersky product is now installed.

How to prevent cataracts naturally

Cataracts - cloudiness in the lens of the eye - are a surprisingly common visual problem with almost everyone over the age of 65 having some degree of cataract formation.
And most people over the age of 75 will experience some visual deterioration as a result of this condition.
With an increasing ageing population, the incidence of cataracts is set to treble in the next 50 years.
This is not good news when you consider that, according to a recent article in the British Medical Journal, cataract surgery is already beyond the reach of many who need it.

However, in recent years there has been increasing evidence that cataracts can be prevented through dietary change and the use of nutritional supplements.
Far from being an inevitable consequence of ageing, it seems cataracts can often be prevented with a few simple lifestyle modifications.
The lens of the eye sits behind the pupil and focuses light onto the seeing part of the eye (the retina). The lens is composed of a transparent, jelly-like material which is rich in protein. Over time, protein in the lens may become damaged, resulting in cloudiness in the lens known as cataract.
Some cataracts are congenital (present at birth), or are related to specific trigger factors, such as steroid drug use, injury, eye surgery, or diabetes. Most cataracts, however, develop as part of the ageing process.
Until quite recently, the cause of age-related cataracts remained a mystery. It is well established that their development is related to damage caused by destructive mole-cules called free radicals.
The cloudiness induced in the lens by free radicals is similar to the change evident when an egg white is cooked. While a raw egg white is transparent, it becomes opaque when the protein within it is damaged during the cooking process.
One lifestyle factor known to increase free-radical damage is smoking. Research published in the Journal of the American Medical Association in August shows smokers have a much greater risk of cataract formation.
The good news is that the risk can be cut by 25 per cent after stopping smoking in the long term.
Free radicals are quenched in the body by anti-oxidants such as beta-carotene, and vitamins C and E.
Theoretically, increasing our intake of anti-oxidants should help to protect our eyes from developing cataracts. The most recent study to look at this association was published last month in the Archives of Ophthalmology.
This showed that individuals taking a multi-vitamin and mineral which contained vitamin C and/or E enjoyed a 60 per cent reduction in cataract risk.
However, because cataracts develop over many years, supplementation needs to be long term to get real benefit. This study showed the benefits of taking nutrients were apparent only after ten years of supple-mentation.
A previous study, published in the Journal of Public Health in America, showed a 27 per cent reduced risk of cataracts through taking a multi-vitamin containing vitamin C and/or E for five years.
More evidence for the protective role of anti-oxidants came in a study which looked at the relationship between vitamin C intake and cataract formation.
This study, dating from 1997 and published in the American Journal of Clinical Nutrition, found that taking vitamin C supplements for ten years or more reduced the risk of cataracts developing by a massive 70 per cent.
While nutrient supplementation is of proven benefit in reducing cataract risk, making informed dietary choices also has a part to play.

Others 5 tips to prevent cataract are:

1. Take a good multivitamin
   
    The Physicians’ Health Study of 17,744 U.S. doctors demonstrated that those taking multivitamins, especially those with high concentrations of antioxidants, had a 27 percent decreased risk of developing cataracts.
   
   
2. Supplement with vitamins A and C
   
     Vitamins A and C are antioxidants that are highly concentrated in the eyes and help protect against the onslaught of free radicals, which is important if you want to prevent cataracts and promote healthy vision. The recommended daily dosages are: 5,000 IU of vitamin A (as beta-carotene) and 2,500 mg of vitamin C.
   
   
3. Make sure you’re getting enough lutein and zeaxanthin
   
    A 2008 study found that older women who had the highest levels of lutein and zeaxanthin were about a third less likely to have cataracts. I recommend taking 15–30 mg of lutein and 2 mg of zeaxanthin daily.
   
   
4. Take bilberry
   
    Bilberry acts as a vasodilator, increasing blood flow to the vasculature of the eyes, and increases tissue and capillary wall strength. In one study of 50 patients with cataracts, it stopped the progression of the cataracts in 97 percent of the cases. The recommended daily dose is a minimum of 30 mg of a bilberry extract standardized to contain 25 percent anthocyanidins.
   
   
5. Take off your sunglasses
   
    There’s no doubt that excessive exposure to ultraviolet light (UV) can damage your eyes. Specficially, it can cause the conjunctiva, which covers the whites of your eyes, to thicken, thereby contributing to the development of cataracts and retinal damage. But wearing sunglasses all the time blocks wavelengths of light that not only nourish the eyes but are essential for overall good health. So let a little sun in your eyes, and make sure you’re getting your antioxidants.
   

How To Prevent The Zika Virus

A preliminary report by the Dallas County Department of Health indicated that a person in Texas contracted the Zika virus via sexual contact with someone returning from Venezuela. While the Centers for Disease Control and Prevention (CDC) has not yet confirmed that the Zika virus was indeed sexually transmitted, finding another mode of transmission beyond mosquito bites would be troubling. With the virus now seen in over 30 countries, the World Health Organization (WHO) has declared an international public health emergency. So is it time to panic and buy some duct tape? No. What, then, should you do?

World Health Organization chief Margaret Chan has declared the growing Zika virus epidemic a global health emergency. (Photo credit FABRICE COFFRINI/AFP/Getty Images)

If you are thinking of avoiding anyone who looks like they have the Zika virus, forget it. You can’t profile people who are infected with Zika. An estimated 75% of infected people have no symptoms. Therefore, to be safe, you’d have to avoid everyone. When present, symptoms usually begin between a couple days to a couple weeks after infection and last no more than a week. It appears that people can remain infectious up to one month after being exposed to the Zika virus. Observed symptoms include a mild fever, skin rash (often on the face), muscle and joint pain, redness and irritation of the eye (similar to “pink eye”) and a run down feeling. Therefore, you can’t really diagnose Zika virus infection by symptoms alone as the symptoms are very similar to many flu-like illnesses. Blood tests do exist, but currently people are not routinely tested for Zika virus. There is also currently no treatment or vaccine for Zika.

So, what can you do to avoid Zika virus infection? If you are traveling to countries with mosquitoes carrying the Zika virus, avoid mosquito bites in a similar fashion as you would when traveling to countries that have mosquitoes carrying the pathogens that cause malaria or Dengue. This includes minimizing the amount of skin you leave exposed (this is not the time to wear a crop top or a Speedo, as opposed to all the other times you should be wearing a Speedo), staying in air-conditioned areas that are free of mosquitoes, sleeping under bed nets if your sleeping quarters may have mosquitoes and using proper insect repellent.

Sort of like wearing too much cologne, insect repellents mask the things emitted by your body that may attract mosquitoes, such as carbon dioxide and heat. You tend to emit more carbon dioxide and heat when you exercise…so avoiding twerking outside and at mosquitoes. Other than holding your breath forever and wearing an ice tuxedo, you can’t really prevent yourself from emitting carbon dioxide or heat. Look for insect repellents with DEET (diethyltoluamide), which tends to be more effective against mosquitoes that carry disease. On this website, the U.S. Environmental Protection Agency (EPA) offers guidance on insect repellent selection.

Without taking the above precautions, you will find it difficult to avoid mosquito bites. In fact, many mosquito bites are undetectable. Just because someone doesn’t have obvious bites, does not mean he or she hasn’t been bitten.

How to Get Rid of Acne Naturally At Home

Acne and pimples are two of life’s most annoying and prevalent skin curses. Most of us have been in a situation where an ugly red spot has appeared the day before an important event or date. The question is: can you do anything about it without having to indulge in expensive medication? The answer is yes! Try some of these simple and natural home remedies to fight off those pesky pimples.

1. Aspirin

Aspirin is an anti-inflammatory so it can be a quick and cheap way to help reduce a pimple. The other plus is that most of us always have aspirin lying around at home. The simplest way to use it is to make a paste with 3 parts water to 1 part aspirin. Once the mixture had thickened take a Q-tip and apply to the aggravated area. The paste will take roughly half an hour to harden and begin to flake off, which will be your cue to wipe the paste off with a west tissue or face cloth.

2. Take a dip

If you have a pool readily available, try going for a swim. Chlorine is known to dry out your skin, which is good news for getting rid of pimples. Just be sure to properly moisturize the rest of your skin and condition your hair to prevent damage.

3. Aloe Vera

This bad boy is a triple threat. Not only does it cool your skin down, which feels great, it reduces the inflammation and redness of pimples as well as removes the oiliness from your skin.

4. Toothpaste

Toothpaste is a good option if you have a mammoth pimple that you want to take care of quickly. It is effective because it contains silica, which is the same substance that can be found in bags of beef jerky to keep moisture out. As such, toothpaste has been know to dry out and reduce the size of pimples over night. Simply apply some to the affected area before sleep and wash it off in the morning.

5. Honey

Honey honey, how you thrill me, ah-hah, honey honey.
In addition to being delicious, honey is a natural antibiotic which makes it perfect for healing and reducing pimples. As an added bonus its stickiness helps to remove excess dirt and impurities from your skin. You can utilize honey by making a simple mask. To do this, mix two tablespoons of the golden elixir with a teaspoon of cinnamon and apply it to your face. Yes, it may get messy. Allow the mixture to set for roughly ten minutes before rinsing it off with warm water.

6. Garlic

I’m one of those crazy people who grows her own garlic, so you don’t need to give me an excuse to use it even more than usual.
Garlic is fantastic for fighting acne due to its high levels of antioxidants, as well as its’ anti-bacterial, anti-fungal, and anti-viral properties. There are two ways you can use garlic to clear up acne. The first is a preventative measure, which is simply by adding more garlic to your diet. This helps your general health as well as purifies your blood, which can help to stop future break outs. For more immediate results, take a peeled clove of garlic and rub it on the troubled area several times a day. If your skin is sensitive, try crushing the garlic and mixing it with some water.

7. Steam

No, not the software. Although I do recommend that also.
Steam can be helpful for treating acne because it helps to open up your pores, which prevents them from being clogged. Steam also moisturizes and detoxifies your skin.

8. Tea Tree Oil

Tea tree oil is renowned for being good for your skin. In addition to this, it also contains anti-bacterial and anti-fungal properties, which makes it highly beneficial for acne treatment. In fact, studies that compare tea tree oil to the acne medication benzoyl peroxide shows it to be just as effective. Simply apply the oil to the pimple or affected area with a cotton wool ball or Q-tip.

9. Cucumber

Cucumber works as an anti-inflammatory, which is why people use cucumber slices to combat puffy eyes! They work just as well for pimples and will help to reduce the angry redness of them. You can make a paste by by combining finely grated cucumber with two to three teaspoons of lemon juice and applying it to your skin. Leave for ten to fifteen minutes before washing off.

10. No Popping!

I’ll admit that I’m guilty of popping a pimple or ten in my time, but you need to try and fight the urge! As tempting and gratifying as it may be at the time, it’s the worst possible thing you could do. Firstly, it further inflames the area which means that it can result in scarring. Secondly, popping causes the bacteria living in the pimple to spread to other pores, thus infecting them too. Ironically, this can easily result in even more pimples. Just don’t do it!

11. Ready your face for steam cleaning

  If your hair falls into your face, pull it back and secure it with a hair tie, head band, or bobby pins. Wash your face with a gentle cleanser, either a non-oil-based product or a plant-oil-based product. Many dermatologists recommend using glycerin, grapeseed and sunflower oils, as oils are best to absorb and dissolve other oils.

• Use your fingertips instead of a washcloth or sponge that could further aggravate your skin.
• Massage the cleanser into your skin for about a minute using a gentle, circular motion. You're not trying to scrub, just help the cleanser loosen and absorb dirt and oils.
• Rinse your face thoroughly with lukewarm water.
• Pat your skin dry using a clean, cotton towel. Never rub a towel over your face, as this could further irritate your skin.

12. Choose your essential oils

  The oils listed here all have either antibacterial or antiseptic properties, meaning they can kill the bacteria that cause acne and prevent the formation of new pimples. You can choose based on personal preference (which one smells best?) or based on your unique situation. If you tend to be anxious or depressed, use the lavender. If you have some pimples (usually bacterial), in addition to blackheads, use an herb with antibacterial properties. If you are battling an upper respiratory infection, use thyme to both treat the infection and break up the congestion with heat.

• Spearmint or peppermint oils may be irritating to some, so pre-test your skin by putting a single drop of it on your wrist and waiting for 10-15 minutes. If there is no irritation, you should be able to use the oil. Start with 1 drop per quart of water. Both peppermint and spearmint contain menthol, which has both antiseptic and immune-boosting properties.
• Thyme boosts the immune system and has antibacterial properties. It also increases circulation of the blood by opening up blood vessels.
• Calendula accelerates healing and has antimicrobial properties.
• Lavender is soothing and can help with anxiety and depression. It also has antibacterial properties.

13. Prepare your steaming water

 Fill a 1-quart pot with water and bring it to a boil for a minute or two. Once the water has been steaming for a couple minutes, add 1-2 drops of any of the listed essential oils.

• If you don’t have the essential oils, substitute with ½ teaspoon of the dried herb per quart of water.
• Once you have added the herbs or oils, let the water boil for another minute.
• After a minute, turn off the heat and move the pot to a comfortable area for steaming. Make sure you won’t have to hunch awkwardly over the pot, as you’ll have to hold that position for a while.

 14. Test for skin sensitivity

  Always be aware that you can develop sensitivity to an herbal oil. Even if you've successfully used oil in the past, retest it every time you steam your face with it. Try each oil for about a minute, then take your face away from the steam for 10 minutes. If you're not sneezing and you're skin isn't reacting poorly, reheat the water and proceed with the steaming.

How To Install Microsoft Office 2016

This is the introduction on how to install Microsoft Office 2016. Microsoft has put out the free download of Office 2016 for Mac public preview, without any Office 365 subscription required. The new software includes support for Retina displays, iCloud syncing, and looks like the versions of Office currently available on Windows and mobile.

Step 1: Download The Install

Once you download the 2.6GB file to your downloads folder, click on the Office Preview Package to get started. You will be guided through the necessary steps to install this software.
Tip: I had to upgrade my OS X because you can't install Office for Mac with any version of OS X below 10.10. To see my tutorial on how to upgrade your OS X.
I also had some internet interruptions on my initial download to my downloads folder and had a hard time opening the package because it did not download the full 2.6GB. Make sure that you fully downloaded the package.

Step 2: Read And Agree To Licensing Agreement

The software license agreement comes in many languages, this one in English. Once you read the agreement, you will have scrolled to the bottom. Click continue to agree.

Step 3: Agree To The License Agreement To Begin Installation

You will then be prompted to agree. Once you do you will select what users of your computer will have access to the software to select the destination for install. You will need 5.62GB of free space to install. Select and click continue.

Step 4: Install Office For Mac

I want all users of my computer to be able to access Office and made sure to have the available space. Now I am ready to install. I click install. I had to wait a few moments for the installation to complete. Then I was notified that the installation was successful. And my installation is complete.

How to Setup Microsoft Outlook 2016

Here are 7 steps setting up Microsoft Outlook 2016:

Step 1 - Open Outlook 2016

Step 2 - Click Add Account

Step 3 - Enter your details

Step 4 - Configure your account

Step 5 - Click More Settings

Step 6 - Enter Root folder path

Step 7 - Complete setup

Step 1 - Open Outlook 2016

Click File in the top-left corner.

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Step 2 - Click Add Account

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Step 3 - Enter your details

• Enter your Name, your Email address and the Password for your email account with One.com.
• Click Next.

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Step 4 - Configure your account

• Wait while Outlook completes the setup.
• Check the box for Change account settings and click Next.

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Step 5 - Click More Settings

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Step 6 - Enter Root folder path

• Click on the Advanced tab.
• Enter INBOX as the Root folder path and click OK.

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Step 7 - Complete setup

• Click Finish, Outlook will now test your account settings by trying to send a test message.
• Press Close when the tests are completed.

Congratulations! You are now done.

12 tips for naturally beautiful nails

You don’t have to visit the salon on a regular basis in order to have beautiful nails. The combination of a well-balanced diet, a thoughtful beauty regimen, and good personal hygiene can give you salon-worthy nails at a fraction of the cost and chemical burden.

1. Use moisturizer

When rubbing lotion or oil into your hands, make sure you work it into the cuticles and nails, too. Regular handwashing or use of hand sanitizer can dry out the skin and nail bed quickly, so try to moisturize after every wash, if possible. Coconut oil is excellent for rubbing into your nails and cuticles.

2. Care for your cuticles

Avoid having your cuticles trimmed during a manicure. Cuticles are meant to be a barrier for bacteria, and cutting them can lead to painful infections. You can moisten and push them back with a cuticle pusher, and trim away only dead pieces of skin.If you’re planning on having a conventional manicure done, then at least protect your cuticles by dabbing with olive oil or almond oil prior, in order to reduce the amount of chemical that soaks in from the polish.

3. Avoid using harsh polish

Nail polish typically contains very toxic chemicals such as toluene, dibutyl phthalate, dimethyl and diethyl phthalates, camphor, and formaldehyde. Fortunately, companies such as OPI, Orly, Sally Hansen, and Revlon make some polishes that do not contain these chemicals, but make sure you read the label carefully before purchasing. You can also buy water-based polishes, which don't last as long but are the safest option out there.

4. Seek out alternatives

There are companies now making less toxic polishes and removers. Check out the following list and take your favorite color along when you go to the salon for your next pedicure.Suncoat
Scotch Naturals
Acquarella
SpaRitual
Deborah Lippman
Priti
No-Miss Nail Care

5. Buff instead of color

It may not be as fancy or eye-catching as color, but a bit of buffing can go a long ways. Take the time to trim, file, and buff your nails properly and you’ll be pleasantly surprised at how great they can look, despite being au naturel. Never saw back and forth with a file because that can weaken your nails. Always file from the outside edge of the nail inward.

6. Choose a good remover

You can get acetone-free remover almost anywhere, which is less harsh on your nails. Priti sells a remover made entirely from soy and corn, and No-Miss has one called Almost Natural that contains fruit acids and vanilla.

7. Eat well

Diet is very important to maintaining healthy nails. Protein is crucial, as are omega-3 fatty acids. Eating foods with vitamin B reduces brittleness; zinc gets rid of white spots; iron prevents ridges from forming; calcium keeps them strong; vitamins A and C prevents dullness and drying. Drink plenty of water to stay hydrated.

 8. Gather supplies

  You'll need a few tools in order to make your nails look healthy and beautiful. You might have to spend a little money to accumulate everything you need, but over time doing your own nails is much less expensive than getting manicures. Here's what you need:

• Nail trimmers
• Nail file
• Polish remover
• Cotton balls
• Buffer
• Cuticle cream
• Hand lotion
• Orange stick

9. Soak your nails in a bowl of warm water

  Soaking your nails softens them and makes them easier to trim. It also makes your cuticles more supple and easier to push back. Soak for about five minutes, until your nails are pliable, then dry them on a towel. 
 

10. Trim and file your nails

 Use nail trimmers to create the nail shape you want, either squared off or rounded. Don't trim too short; you want to leave a white crescent on each nail. This extra length protects your nail beds and looks pretty, too. Use a nail file to neaten the edges and smooth out the shape of your nails^.

• When you're using a nail file, move it in one direction across the tip of your nail. Don't scrape it back and forth, since this damages your nail fibers.
• Avoid using a file to make your nails shorter; always start with a nail trimmer, then use the file just for shaping purposes.
• Do not round the corners down into the sides of the nail bed, because this can cause ingrown nails, especially on the big toes.

11. Push back your cuticles

  Dry your nails and apply a cuticle cream. Let the cream soak in for about three minutes, then use an orange stick (or cuticle pusher) to gently push back the cuticles, the skin growing at the base of your nail. This makes the shape of your nails prettier and prepares them for an even coat of polish. Wipe off the cuticle cream when you're finished.

• Never force your cuticles back, and never trim them. Cuticles are there to prevent infection, and cutting them will leave your fingers prone to getting red and sore.
• If you don't have an orange stick, try using a binder clip or another item with a flat edge. Just make sure not to use anything sharp.

12.Buff your nails

  Use the rough side of your nail buffer to buff your nails, gently running it across the surface of your nails in one direction. Next switch to the medium-grade side and repeat the process. Finish buffing with the smoothest, finest side to add sheen to your nails. Don't grind down the surface of your nails too much. You don't want to thin out your nails. The goal with buffing is just to create a smooth, shiny surface.

How to Install Office 2013

Here are the introduction to install office 2013 on your computer:



The recent release of Office 2016 adds some useful new features and improvements and is now the default version installed as part of Office 365. However, if you want to install Office 2013 instead or on another machine, that is easily done.
Sign in to your Office 365 account by visiting https://www.office.com and clicking “Sign in” in the upper-right corner of the webpage.



You may see the page pictured below. If you purchased your Office 365 subscription using a work or school account, sign in on that page. However, if you used a personal Microsoft account, click the “Sign in with a Microsoft account” link and sign in on the resulting webpage.



Once you’re signed in, click the “My account” link at the bottom of the page.



Under “Install”, click the “Install” button.



In the “Install Information” section of the “My Office Account” page, click the “Language and install options” link.



Click the “Additional install options” link.



On the “Additional install options” screen, select “Office 2013 (32-bit)” or “Office 2013 (64-bit) from the “Version” drop-down list, depending on the type of system you’re running.



Click “Install” to download the appropriate installation file.

In Chrome, the file is downloaded to the default directory or you’re asked where you want to save the downloaded file, depending on your settings. To run the file, click the filename in the “Downloads” panel at the bottom of the window.
NOTE: In Firefox, you can choose whether you want to save downloaded files to a location you specify or whether you want to be asked for a location every time. Other browsers may have different options for download locations for files.



NOTE: You can also directly access the downloaded file using File Explorer.



A User Account Control box may display asking you for permission to install the application. Click “Yes” to continue installing Office 2013.



An banner displays while Office is “Getting things ready…”.



Office 2013 is then installed in the background and may take a while, depending on the speed of your Internet connection.



When the installation is done, the following “Welcome to your new Office” dialog box displays. You can either go through some screens that help you finish setting up Office by clicking “Next” or you can close this dialog box by clicking the “X” button in the upper-right corner.



NOTE: You cannot install Office 2016 and Office 2013 on the same computer.

New Treatments in the Complicated Patient with Type 2 Diabetes and Hypertension

I assume most of you have something to do with the kidney. In my regular life I come close to nephrologists only when I need their help to dialyze a patient with poorly treated diabetes. I do hope that by the end of this exercise we learn how to do a better job and reduce the number of patients who land in the dialysis center.

Nobody doubts anymore that there is a diabetes pandemic in the world. In fact, Dr. King of the World Health Organization (WHO) has projected that by the year 2025, there will be at least 300 million persons with diabetes worldwide; that would roughly represent a doubling of the rate from about the year 2000. So, there is an epidemic, and the vast majority of persons who develop diabetes will have type 2 diabetes. We also are seeing increases in the prevalence and incidence rates of type 1 diabetes across the world, but the magnitude of increase is nowhere near what we see with type 2.

The overwhelming explanation for the diabetes pandemic is attributable to type 2 diabetes; the natural history and pathophysiology of this disease has been increasingly understood. We now know that in persons selected by their genetic makeup and stressed by the environment, very early changes begin to occur in glucoregulatory physiology that translate to insulin resistance. Even in that early stage of "dysglycemia" -- where the blood glucose numbers are still, technically, within the normal range; and with regard to diabetes diagnosis, they are nondiabetic -- you begin to see changes in lipids that are unfavorable, specifically small decreases in high-density lipoprotein (HDL), the protective cholesterol, and increases in triglycerides. About that time, people also begin to accrue increases in both systolic and diastolic blood pressure numbers but they still do not qualify for diabetes diagnosis. With insulin resistance comes a demand for greater and greater secretion of insulin. The natural biologic response to a resistant state is overproduction of the signal hormonal ligand; the beta cells of the pancreas are called upon to work harder and harder to produce more and more insulin. This insulin-resistant hyperinsulinemic phase is really a prodromal phase for future diabetes, a prodrome that "crosses the Rubicon" when people begin to wake up with fasting glucose greater than 99 mg/dL. The individual whose fasting glucose reaches 100 mg/dL is no longer considered normal; 100 mg/dL in the fasting state now has a new name, impaired fasting glucose (IFG), and 126 mg/dL, as you all know, is diabetes in the fasting state. We have people in these prediabetic stages of IFG and impaired glucose tolerance (IGT), and they stay there for variable periods, depending on genetic makeup and other stressors. Some may evolve rapidly to overt type 2 diabetes, others may not progress that rapidly, and yet some others might even recover from this intermediate stage. We call that reversion to normal glucose tolerance. In those who are destined to move on to diabetes, we see the glucose numbers creep up into diagnostic ranges, and they are identified as patients with diabetes and treated accordingly. This is a conceptual slide from a review article by LaSalle, who is a primary care physician with great interest in diabetes and has been honing his skills in the area of diabetes research. Notice that eye damage and kidney damage -- the type you deal with in diabetic nephropathy, as well as diabetic neuropathy, the so-called, "microvascular complications" -- do not begin to occur until after the hyperglycemia has occurred. They are glucose-driven, glucocentric complications. However, long before the clock starts ticking for microvascular complications, you notice the beginnings of risk factors of macrovascular disease, such as dyslipidemia and hypertension, which together with other atheroinflammatory mediators, will set the stage for atherosclerosis. So, this occurs at an earlier time point.

But, getting back to the diabetes epidemic, and specifically to the pathophysiology of type 2 diabetes. We now know that there are multiple contributors to the eventual occurrence of hyperglycemia, chief among these is a change in tissue response to insulin. Insulin is the ultimate anabolic hormone that has major influences in the metabolism of glucose, protein, fatty acids, salt and water, and even memory facilitation in the central nervous system, among others. Yet, in persons who have inherited diabetes -- a set of diabetogens from their blood line -- who then also are confronted by environmental challenges, such as obesity or physical inactivity, these risk factors collude to uncover a state that, for lack of a better description, is called insulin resistance. That state is all-pervasive; every cell is involved in that perturbation. The simplest construct for understanding insulin resistance, almost a simplistic approach, is to measure insulin-stimulated glucose uptake by the tissues. If you did that years, and sometimes decades, before the occurrence of type 2 diabetes, individuals at risk might begin to fail that test -- the insulin sensitivity test, where you measure impairment in insulin-stimulated glucose transport. But, that is only one way of identifying insulin resistance. There are many other pathways of insulin signaling for which we, currently, do not have routine measurements or convenient tools to probe at a clinical level. This insulin resistance precedes the occurrence of type 2 diabetes, but it does not go away when the diabetes has occurred. It hangs in there and continues to negate the effect of any treatments we bring to bear on the diabetes, unless such treatments specifically address the resistance; and that is a very important therapeutic point to make. Now, in addition to insulin resistance, the beta cells of the pancreas play a leading role in allowing diabetes to occur. After all, you can induce all the insulin resistance in the world in a given subject; but, if their pancreas responds appropriately, by secreting tons and tons of insulin, the blood glucose will stay in the normal range. So, it is the failure of the beta cells of the pancreas to adequately compensate for progressive insulin resistance that becomes the denouement, the ultimate straw that breaks the proverbial camel's back and allows hyperglycemia to occur. So, insulin resistance is necessary, but not sufficient, to cause diabetes. A second hit, a second defect, residing within the beta cells of the pancreas allows for the diabetes to manifest; and that defect in the beta cell itself is now believed to be largely inherited. So, people in diabetes families would have a set of genes that predicts the insulin resistance and, perhaps, another set that predicts apoptosis, or increased cell death, within the Islets of Langerhans that prevents them from mounting a sufficiently robust insulin secretory response. Many will not know this intuitively, but it is true that gastric emptying rates are accelerated in people with diabetes. When you encounter diabetes in the context of gastroparesis, you tend to think that the bowels are sluggish in people with diabetes; but, actually, the primary motility defect in diabetes is accelerated gastric emptying. Some of the newer agents that have been introduced have actually worked on diabetes by slowing down the gastric emptying rate. Some of the incretin agents work on that. The other defect that we are beginning to understand in diabetes comes out of the adipocytes; lipolytic products like glycerol, free fatty acids can be used by the liver to produce more glucose molecules. Other adipocytokines that come out of the fat cells also are turning out to be very bad for glucose metabolism, by inducing insulin resistance and other processes. Finally, the liver plays a key role in the final pathogenesis of type 2 diabetes. Remember that the liver is a glucose factory, producing on average 1 mg glucose/lb of body weight/min. When people have type 2 diabetes, their average glucose production rate increases from the normal value of 1 mg/lb/min to 2 to 3 mg/lb/min. There are 1440 minutes a day; when you do the math, you can readily appreciate how much glucose is coming out of the liver. That number can be doubled or tripled if you are dealing with a diabetic patient. Interestingly, all of these pathophysiologic defects in type 2 diabetes also are veritable targets for drug development. We have at least 1 drug on the market that will be addressing each of these targets.

Beta Cell Defects and Diabetes Outcomes

Let me spend a moment on the beta cell defect, because it is really the Achilles' heel of type 2 diabetes pathophysiology. If you take away somebody's pancreas, you convert them immediately to diabetes; if you do a total pancreatectomy, if you deprive a system of insulin, that system immediately becomes diabetic. But, if you increase insulin resistance inordinately highly, you still do not have 100% straightforward diabetes, as long as the beta cells of the pancreas are rising to the challenge. The failure of the beta cells to rescue nearly 20 million Americans who already have developed diabetes and 300 million people in the world who will develop diabetes by the year 2025 is an important research matter. We are not quite sure why the beta cells are failing. We do know that the cell mass decreases and that the mechanism of cell mass loss is through programmed cell death, or apoptosis. These triggers for the apoptosis, however, are not well known, but we do have candidates. Time will not permit me to really flesh out this slide, but suffice it to say that current research has accorded priority to elucidation of the mechanism for beta cell death in type 2 diabetes. Numerous targets, including immunologic targets, lipotoxicity, and hyperglycemia itself, have been identified as a signal for cell dysfunction. Above certain thresholds of ambient blood glucose levels, the beta cells begin to take a hit; we call it glucose toxicity. They begin to be affected down to the genomic level, where the transcription and translation of the insulin gene becomes impaired by ambient hyperglycemia. That is a reversible cause of beta cell dysfunction.

If we go back to the diabetes epidemic, one of the most worrisome signs from the clinical research field is that one does not need to have big scale increases in blood glucose to begin to suffer dire consequences. There is a study coming out of the United Kingdom called the European Prospective Investigation Into Cancer (EPIC). It is a cancer-focused study, and in one of the study sites, in Norfolk County in England, they had enough measurements of biochemical values, glucose values, over several years to allow analysis. What you see on the screen is cardiovascular mortality, outcomes data, on the basis of shifts in blood glucose levels captured by the hemoglobin A1c within reasonably normal ranges of life. If you look at physiologic ranges of hemoglobin A1c, people without diabetes score from about 3% to at most 6% on that test. Within up to 5.5% A1c, you are seeing a doubling of mortality from coronary heart disease, compared with people whose A1c is less than 5%. By the time you get into the early diabetic range, A1c of 7% or higher, the increase in the risk of dying from coronary heart disease is 7-fold. If you go to all-cause mortality, you see the same "staircase effect," where every increase within the normal range, an average glucose, is predicting a measurable increase in the risk of mortality. This is a very powerful study that draws attention to early dysglycemia, early escape from normal glucose, being cardiotoxic in ways that were not previously fully appreciated.

When somebody already has the diabetes and then suffers a heart attack, we know that the consequences are disastrous and the prognosis is horrendous. If you do the 200-day mortality analysis for people with or without diabetes who have suffered a heart attack, those who do not have type 2 diabetes (or any diabetes for that matter) and whose in-hospital blood glucose average is lower than 200 mg/dL have the best survival. Persons who have type 2 diabetes and whose glucose exceeds 200 mg/dL have at least a 30% decrease in survival within 200 days. Look at these data. These are folks who did not know they had diabetes. The worst category were people with no known history of diabetes. You get a heart attack, and in the course of that hospitalization, your glucose runs in the 200 mg/dL range -- most likely the 5.5 million Americans walking around with diabetes, but do not know it yet -- those undiagnosed diabetic folks get a heart attack and get in there. Their glucose is not addressed; because they do not have the level of diabetes in the entry history and physical (H and P), nothing is done to address glucose. Look at their survival -- 50% dead in 200 days. So, there is a gradation of glucotoxic effects manifesting in the cardiovascular system that precedes the clinical diagnosis of diabetes, and it then amplifies the risk of dying from diabetes if an event has occurred.

Monodrug vs Combination TherapyMonodrug vs Combination Therapy

Let's switch gears and address the better part of my talk -- what are we going to do about it, because so far I have been painting gory pictures of horror stories happening to our patients. The good part is that we have things to do about it. I mentioned earlier that most of the pathophysiologic contributors to type 2 diabetes themselves present veritable targets for intervention; so, you look at the level of myocyte where insulin resistance is most richly expressed. We do have agents that can reduce insulin resistance and improve insulin sensitivity. The thiazolidinediones (TZDs), and to some extent metformin, can improve peripheral insulin sensitivity. If you look at the excessive glucose production in the liver -- which you recall is 2- to 3-fold increased in type 2 diabetes compared with nondiabetic controls -- we have agents (metformin primarily, but all the TZDs in full dosages) that can be shown to reduce hepatic glucose production. The adipocyte issue is most responsive to TZDs, where the average fall in free fatty acid recorded can approach 47%, 50% reduction from baseline; that is a major target for TZD action. There is insulin secretion, of course; we have had 70-plus years of familiarity with using secretagogues to treat type 2 diabetes. They operate on diabetes by stimulating insulin secretion. Of course, the caveat is that there must be residual beta cells for them to work. That is why we do not prescribe them routinely to kids with type 1 diabetes, who are bereft of all beta cell function. But, if there are some cells left, the secretagogues can stimulate them to release some more insulin, at least for some time.

The bad news is that the more medications we get approved in this therapeutic space, diabetes management, the worse the national hemoglobin A1c appears to become. That paradox has not been fully explained to my full understanding. But, look at the report cards. Clearly, well below 50% of our patients with diabetes are getting their hemoglobin A1c controlled to the minimally acceptable target of 7% or lower. The American College of Endocrinology actually asks for 6.5%, and there are studies that are testing 6% as the proper goal. So, we are not really accomplishing a lot by way of control, and that is not an isolated lack of achievement in diabetes, even in blood pressure management. If you combine diabetic folks who also have hypertension and high cholesterol, in whom all 3 conditions are treated to excellent degrees, you are talking about less than 10%. It has been a challenge.

The challenge can be addressed, in my opinion, by adopting a deliberate policy of combination drug therapy. One of the weaknesses of chronic disease management is the patient factor. The patient adherence over prolonged periods of time is challenging. We can "sneak beneath radar detection," if you will, by loading on more than 1 chemical to the pill, so that, when patients think they are taking 1 pill, they actually are taking multiple medications. That may be one way to address the major problem of lack of excellence in glucose control. Whenever dual combination therapies have been pitched against monotherapy, the outcome has always been predictable. Here you have the glyburide/metformin combination pill tested against metformin alone in higher dosages (more than twice as much as was loaded here); or glyburide alone at least twice the dose. "Half and half" of these drugs will get nearly 80% of your subjects at the American Diabetes Association (ADA) target of A1c; whereas, individual drugs titrated to much, much higher milligram dosages failed to match the combination product.

That is an approach that we can increasingly use; but are we using it? Far from it. This study came out of the Kaiser Permanente group, a group model health maintenance organization (HMO), in fact, the granddaddy of all HMOs, where everybody is insured and has access to all kinds of specialties or interventions. In that study, Dr. Brown looked at the charts of diabetic patients whose doctors have registered an A1c of 8% or greater on 1 occasion, and he looked forward in the chart to when an appropriate action was taken. An appropriate action being defined as switching to another drug or adding another diabetes drug onto the one that did not seem to be working that well, because the patient's A1c was high. It turned out that it took too long for any change, any response to high A1c, to be recorded or to be documented -- more than 1 year, whether patients were initially on Glucophage (metformin) or on a sulfonylurea. The physicians were waiting too long. To the extent that Kaiser Permanente doctors are usually well trained, often multiply board certified, and drawn from a cross-section of the US demography, they do not mean ill, they are not incompetent -- to that extent these numbers reflect national habits. I have seen data, not presented today, where a different set of practitioners was audited and the numbers were not much better than you see. People are waiting longer than a year to address high A1c levels. We need tools also. When we advocate combination therapy, we need tools that can get patients close to the goal. The national average A1c is still hovering uncomfortably closer to 9% and 10%, rather than to the 6.5% that we desire.

Effectiveness of Combination Therapies

One of the newer products, a drug that combines rosiglitazone and metformin in a fixed-dose combination pill, recently has been shown to give us as much as a 4 percentage point reduction in hemoglobin A1c when used as first-line therapy for individuals selected for their initially high hemoglobin A1c levels. Now, I must add that that product (rosiglitazone and metformin, marketed as Avandamet) has not yet been approved for initial therapy, but it is approved for later therapy and combination therapy. But this study is so convincing that I would be surprised if that indication does not become available soon, because 4 percentage points mean we can restore many of our patients close to the 7% A1c goal.

Similar data exist, proving the point that combination therapy always delivers better quality care than single agents. Again, I do not want to belabor the point, but, the percentages reaching both the American Association of Clinical Endocrinologists (AACE) goal and the ADA goals are higher when the combination product was administered.

Similar studies have used a different thiazolidinedione, a drug called pioglitazone (marketed as Actos). When combined with metformin, it can give you a nice decrease in hemoglobin A1c. Metformin is combined with a sulfonylurea drug called gliclazide (not available in this country but widely used in Britain and continental Europe). Again, the faster, more rapid action of sulfonylurea is evident, but the long-term impact is similar between the 2 drugs. Combination therapy works; that is the bottom-line message.

In a more recent study, Rosiglitazone Early vs Sulfonylurea Titration (RESULT), we really have the point crystallized for us. In this study, individuals were divided into 2 camps. One-half received titration of a single sulfonylurea drug, glipizide (Glucotrol), to a maximum dose of up to 40 mg/day. The other group had half of the maximum dose of sulfonylurea with rosiglitazone added. Again, you have seen the hemoglobin A1c response to the combination product being exceedingly greater.

Insulin resistance is the bane of type 2 diabetes, and decreasing that resistance is a target. Rosiglitazone/sulfonylurea combination group did that, whereas sulfonylurea alone did not have an impact on the insulin resistance.

If you look at the same data using pioglitazone, again, TZDs do improve insulin resistance. Sulfonylureas do not work on diabetes by altering insulin sensitivity; they are secretagogues. This is a very well-known point, but from time to time you may hear presentations that do not fully accord with the reality. So, no sulfonylurea on the market has an insulin-sensitization property.

Summarizing Combination Therapy

Advantages of TZD-containing preparations have been written about in the literature, but we need studies

The maximization of a single drug often is not a winning strategy in diabetes management. That has been repeatedly proven for us. Early recourse to combination therapy is a smart move. The use of fixed-dose combination strategies might ease patients into the treatment by optimizing compliance, as compared with their having to open multiple pill bottles and take them. Aggressive treatment of diabetes is really the way to go.

Cardiovascular Implications of Thiazolidinedione Therapy

I want to show you some quick clinical trials, one that recently has concluded, others that are coming. The TZDs, when you look at them, offer so much theoretical benefit that one often jumps to the conclusion that they ought to be part and parcel of every diabetes regimen. Well, before we do that, we need evidence, clinical evidence.

The study here is the PROspective Pioglitazone Clinical Trial in MacroVascular Events Study (PROactive study) of patients with type 2 diabetes who have already had cardiovascular or microvascular events or problems and have multiple risk factors. They were treated to "standards of care" and then one-half were given pioglitazone; the other half were not given pioglitazone, but a matching placebo. They were followed for 36 months. You see a 10% decrease in the composite primary end points, which included myocardial infarction (MI), dying from any cause, cardiovascular accident (CVA), and acute coronary syndrome, among others. This benefit accruing to the TZD barely missed statistical significance, and for that reason we say it was not significant. However, 10% fewer events is clinically meaningful, 1 in 10 fewer events. Why was the primary end point not significant? The point being made here is that perhaps the group of patients enrolled for the study were too far gone. Remember, macrovascular complications begin before clinical diabetes. The presence of diabetes is equivalent to 1 heart attack. You saw from the data of Haffner and colleagues that diabetes is a coronary risk equivalent, not a risk factor. Diabetes, plus events, plus additional risk factors; therefore, it must be a tertiary prevention study. So, it is even highly impressive that, despite that late advanced stage, a TZD study is still able to show some benefit. In fact, when you look at the secondary end points, the prespecified secondary end points, you get a bigger event reduction and statistically significant numbers.

This is time to acute coronary syndrome.

This is time to fatal or nonfatal MI. So, I think that the story continues to look rosy for TZDs. Other studies in the works have learned from this study and this design. They are targeting earlier-stage individuals before any heart attack, sometimes even before diabetes. I will show you some of those studies.

Management Issues With the Thiazolidinediones

People gain weight on TZDs. Part of the weight gain is fluid; the other is actual fat cells being accumulated. That has discouraged many practitioners from considering these agents. It also has demoralized some patients from staying on them.

For that reason, a panel was put together by cardiologists and diabetologists to look into fluid retention issues with regard to thiazolidinediones. Here is a summary of the recommendations. I commend the full article to you to look up, but it is really reassuring. We are quite sanguine with the condition that less than 1% of congestive heart failure is triggered by TZD monotherapy. Even for those who are edematous, the edema will not be due to heart failure in the vast majority of subjects. However, if cardiac status deteriorates and crackles begin to be felt in the lung bases, or shortness of breath occurs, or a cardiologist confirms that there is a worsening of heart failure, the drug should be stopped. Indeed, no TZD should be commenced in a patient who is New York Heart Association class III or IV at baseline. What happens when somebody gains some fluid and has demonstrable edema on a TZD? What do we do? Right now we have been ad-libbing and empirically trying one diuretic or the other, or a drug holiday.

A study is now available that directs attention to what may work and what may not work. In this study (using hematocrit dilution as a surrogate for fluid expansion, volume expansion), 381 patients with type 2 diabetes being treated with sulfonylurea alone or sulfonylurea and metformin, were then given a TZD, rosiglitazone. Nearly two-thirds of them developed fluid expansion, as indicated by a dilution of the hematocrit. They were then randomly assigned to take furosemide, a loop diuretic; hydrochlorothiazide, a thiazide diuretic; Aldactone (spironolactone) an aldosterone-inhibiting potassium-sparing diuretic; or stop the TZD and see what happens to the fluid retention.

This is the first of its kind, of therapeutic studies, for TZD fluid retention. What became very clear was that an ordinarily weak diuretic in the grand scheme of things, spironolactone, proved to be the most potent in preventing fluid retention on a TZD, followed by thiazide diuretic;. The loop diuretic, furosemide, was without significant benefit, and compared with continuing the rosiglitazone, giving furosemide (Lasix) did not change things much. Stopping the rosiglitazone was moderately effective in limiting edema; but the best results came when you continued the rosiglitazone and you gave a 25 mg dose of Aldactone. So, that is something we can use.

Safety-wise from the RESULT study, emergency room visits decreased as did hospitalization rate when individuals in the TZD, rosiglitazone/sulfonylurea arm were compared with those whose diabetes treatment was a single drug titrated to the maximum. The mechanism is not very clear, but it is good news and reduced cost.

Studies of Early-Stage Diabetes

In the home stretch, I want to show you what is in the works. You have seen this graph before. I told you that, right up to this point, blood tests will not show diabetes in any of your patients. In this early stage, we begin to see IFG or prediabetes, and we have had a paucity of studies that have intervened in that early stage. The PROactive study went beyond late diabetes, for diabetes plus event, to see if a TZD would change the natural history. What we have are 2 powerful studies that are on the horizon of being completed and one about to be presented. The "A Diabetes Outcome Progression Trial" (ADOPT) trial goes a little later into early diabetes.

The Diabetes Reduction Approaches With Ramipril and Rosiglitazone Medications (DREAM) trial is targeting and has enrolled prediabetics, completely nondiabetic people in the IFG or IGT range. They are being followed for diabetes as an outcome, as well as others (long list of coronary, cardiovascular, and total life outcomes, mortality, etc). These studies are going to be very valuable in the way we approach diabetes and the way we decide to intervene early, and what tools we use for early intervention. In the DREAM trial you have ramipril, an angiotensin-converting enzyme (ACE) inhibitor, being used alone or in combination with rosiglitazone, which is also being used alone or in the combination. Then, you have double placebo; it is a 2 X 2 factorial design. They are being followed after enrollment. They will stay on protocol a maximum of 5 years and then be washed out.

A variety of outcome measurements, including diabetes, coronary events, stroke, and macrovascular disease are being tracked. This study is at an advanced stage of completion, and we will hear results from it before long. It is powered to the extent of 90% power to detect a 22% reduction in the intervention arm, so it is well designed.

In ADOPT, (this is a very busy slide), the crux of this trial is that individuals recently developing diabetes, less than 3 years (on average only 8 months of diabetes history) would immediately be randomly assigned to take either glyburide, metformin, or rosiglitazone, representing the 3 most widely used classes of oral antidiabetic agents.

They will then be followed for an end point that consists of a strictly and rigorously defined failure of monotherapy. We will try to determine which one of these 3 drugs will carry the most patients the farthest along in a state of good control. If that result comes to the finishing line and we have the data, we will be able to share with each other what is the best initial oral agent to introduce shortly after diagnosis of type 2 diabetes on the basis of the evidence.

Finally, I have told you that there is a diabetes epidemic raging. There is no sign of a crest or a plateau at all. It is associated with a galaxy of complications that conveniently can be divided into small-vessel and large-vessel complications. The large-vessel complications are what kill our patients, the heart attacks and strokes. They occur even before the diabetes has become clinical grade, and they are now the target of antidiabetic interventions, not just the glucose. We have been overly focused on glucose outcome measures. We are now expanding and demanding more of our diabetes drugs. What more can we do for our patients with diabetes besides lowering their glucose? Would we prevent the heart attack, etc? Studies are on the horizon that will tell us that.