Posted on October 10th, 2013 59 comments
I recently encountered a problem with my 1999 Dodge Durango’s transmission that was repaired by replacing some sensors. Whenever I discover the solution to a problem I’m having and figure that there are a number of others who may be having the same issue, I like to post the discovery on my blog.
I purchased my Durango new and it has been the most reliable and useful vehicle I’ve ever owned. I love it. So when the transmission started acting funny after about 130,000 miles, I began to think my luck had finally run out. I was impressed lately when I took it to a Grease Monkey and learned that one of their other customers owns 2 Dodge Durangos of the same vintage as mine and each was approaching 300,000 miles with no major issues.
The transmission problems were especially worrisome because I’ve recently acquired a light weight camper (a 16′ Scamp) and have begun taking it on camping trips. I expect to be using it a lot in the future and that will include towing it up some pretty steep grades in the Rocky Mountains here in Colorado. So I need a vehicle I can rely on to handle the task.
The issue I was having was most noticeable when I was starting out from a dead stop. The vehicle seemed to surge back and forth shifting up and down, with the RPM climbing and falling. It would do this for as long as I held the accelerator in the same place. It was almost like a positive feedback loop. But if I stepped down harder on the gas, the problem seemed to go away, instead of getting worse, which wouldn’t generally happen if something inside the transmission was at fault. When your transmission is sick and you ask more from it, it usually demonstrates the problem with even more enthusiasm. But that wasn’t happening in my case. It seemed like it couldn’t decide whether it needed to upshift or downshift at a particular speed which was in the 10-15 mph range.
I started searching for Dodge Durango transmission problems on Google and came across a YouTube video that showed a similar issue, except this guy was having his problem at 70 mph where the vehicle kept dropping into and out of overdrive. He said in his research he had read about transmission problems that could be related to both the throttle position sensor and the transmission speed sensor which are both relatively inexpensive and easy to change yourself. His video goes into detail on how to change the throttle position sensor and it looked quite easy.
I also found a website that talked about how to test the TPS using a volt meter. However, I found that the voltages were impossible to measure because the plug that connected to the TPS is all sealed up. So I reasoned, based on the description of the test, that the throttle position sensor was a simple potentiometer and the way to find a problem with it was to rotate it while watching the resistance level. By removing the plug, I was able to get alligator clips on the potentiometer’s left and center conductors and I carefully rotated the potentiometer from idle to maximum throttle by rotating the linkage on the throttle body. Ideally, it should read from about 800 ohms to 5 K-ohms and increase consistently while rotated in one direction.
Instead of smoothly increasing in resistance, I noticed a point around 1200 ohms where the resistance would increase, but then go DOWN about 200-300 ohms for a while, and then come back up even though I continued rotating in one direction. This defect would cause the voltage to do something similar, so I reasoned that the TPS was a likely candidate to be changed first.
These sensors are easy to find in local auto stores like O’Reilly, Autozone, NAPA, etc.. where they keep them in stock. My web search on the Autozone site assured me that the TPS333 (the model my 1999 Durango 5.9L used) was in stock at my local Autozone store. I picked it up for $34 including tax. It came with extra mounting screws, an O-ring, and a gasket. Although my existing sensor had no gasket, I figured it wouldn’t hurt to install it. It was very simple to remove the old one and replace it with the new one using a Torx T-25 driver. The only ‘tricks’ were that I needed to press in on a latching mechanism to remove the plug and that you have to rotate the part slightly as you install it to get the shafts to mate.
I rotated the linkage by hand to make sure it moved correctly and then I took it out for a test drive. At first, I thought that this had completely fixed the issue. However, it came back after a while so then I tried replacing the transmission speed sensor, a part that costs around $20 and requires a bit more effort to replace. It’s on the driver’s side of the transmission housing and I found it necessary to remove the plate that protects the transmission in order to get a wrench in closer to it. After I replaced that item, I noticed no difference.
I continued to drive the vehicle for a few more weeks and noticed that a new problem had emerged. Sometimes while accelerating, the transmission wouldn’t want to shift into a higher gear. It was frustrating while attempting to achieve highway speeds only to see the tachometer approach the red line. Usually, I could get it to shift by dropping it into 2nd gear with the shift lever, then back into drive and it would usually shift properly after that. This was an intermittent problem too, one that I feared would be hard to diagnose and fix.
The only other candidates that I could think of based on my research were the governor solenoid and governor pressure sensor. Unfortunately, these parts are inside the transmission and are a bit more expensive (about $80 for the sensor and $120 for the governor solenoid). Of course, that meant dropping the pan which is a messy job. I knew that the transmission was due for an oil change, and that I hadn’t ever had a proper oil change where they could access and change the filter (most shops today rely on a ‘transmission flush’, which means they suck out the old fluid and don’t actually change the filter). So I figured that I could combine a transmission fluid and filter change at the same time the governor solenoid and its sensor could be changed so I could more easily rationalize paying nearly $200 in labor to a shop instead of doing it myself.
I took the vehicle to the local AAMCO shop and explained what was happening and they agreed to test drive it with a scanner so they could monitor transmission oil pressure. What they found was that the pressure never got above 30 psi and this was causing erratic shifting, indicating that there was something wrong with the governor solenoid or its pressure sensor. These parts are nearly always changed at the same time since if one is bad, the other is probably also worn and you need to drop the pan to get to either one so it just makes sense to do them both at the same time.
I am happy to report that after spending another $450, the transmission is back to normal, shifting precisely when it should and hopefully ready for another 135,000 miles before needing any repairs. In the 15 years that I’ve owned this vehicle this is the only repair I’ve other than routine maintenance and since the vehicle was paid for long ago, I don’t feel too bad because people who replace vehicles every few years can end up spending that much monthly on a loan or lease payment.
In reading through several forums, I read a horror story where a Dodge dealership wanted to replace the entire transmission for a similar problem for around $4000 but the person declined and found fixed it by replacing the throttle position sensor. So I think it makes sense to try with the easy/inexpensive fixes first and then work up to the more difficult and expensive parts. At the least, you’ll have the peace of mind that all your sensors are good as new.
So if you have a Dodge Durango or Dodge truck based on the same chassis and you’re having transmission issues like I described, you may want to change these sensors to see if the fix works for you too. There’s too high a temptation for a dealership or transmission shop to want to ‘over repair’ and hence over charge for a simple issue like this.
Posted on October 12th, 2012 No comments
I’ve owned an Etymotics ER6i in-ear headset for several years now and have been very satisfied with it. I use it for motorcycling, bicycling, mowing the lawn, and any other activity where ambient noise would otherwise drown out the audio from a standard set of earbuds.
Recently the left earphone began cutting out. By wiggling the wires near the plug I determined that the problem was near or inside the plug. I briefly contemplated purchasing a replacement headset, but then I recalled how much they cost, and it was close to $100.
There were a few resources on the web that showed how to fix a bad connection inside the etymotics earbuds, but I found nothing about how to replace the plug, so I decided to write up my experience here.
I already had a solder-on 3.5 mm plug in my parts bin and, although it was a 4-conductor plug, I figured it would work fine with my iPhone, since it uses a 4-conductor jack to mate with the Apple headsets with integral microphone. I just wouldn’t need to solder anything to the microphone ring. If I didn’t already have a plug, I would have used a 3-conductor stereo 1/8″ (3.5 mm) plug, which is available at RadioShack for a few dollars.
The ER6i cords are independent, but I didn’t know what to expect when I cut them off and stripped them. If I had to deal with coaxial braid, that was going to be a pain, but upon cutting the plug off and stripping the wires, I was pleased to find that each cord contained a pair of conductors, both made with fine stranded wire. Each cord had one wire that was color coded along with a bare copper wire carrying the ground. Upon some testing, I found that the red and green wire carried the right and left channels, respectively.
The green and red stranded wires are coated with an insulating material much like magnet wire that’s so thin you can see through it so even though the colored wires looked metallic and like they would be conductive, they were not. You need to tin the colored wire with a small solder blob to simultaneously burn off the insulating material and make a point where you can solder to. I was worried that the red/green wires would touch each other or the ground wire and short, but they won’t short as long as you don’t tin too much of the insulating material.
This is what the wires looked like before I soldered them into the plug. The bare copper wires from each cord are twisted together and will be soldered to the ground lug.
You need to use an ohmmeter to confirm which solder tabs are connected to the rings and tip of the plug prior to connecting each wire with a small amount of solder. I found it best to put a small amount of solder on the wires and on the solder tabs on the plug first and then just bring the wire and lug together and touch it with a very sharp-tipped soldering iron.
It was great to have a working set of earbuds again and if it ever breaks, I won’t hesitate to repair it again.
Posted on June 12th, 2012 1 comment
In the past few months I’ve run into a number of people who have experienced problems with their laptops running hot. I had an HP/Compaq nx6110 laptop sitting in a drawer that I recalled had been exhibiting the same issue. I wanted to loan it to my nephew to use during a visit and I thought I’d take the opportunity to put in a new battery and check to see the if I could find the root cause of the overheating issue.
I had checked a number of sites on the web that talked about overheating issues with laptops, but none of them talked about the potential for the fan/heatsink assembly to collect dust and block the airflow through the heatsink. If you think about it, most laptops operate like a vacuum cleaner in that they suck air up through a hole in the bottom of the case and blow it out the side. The air must flow through a radiator with fins that can collect lint, dust, pet hair and anything else that it might find in ample quantities when the laptop is placed on a carpet, blanket, or your lap. So the odds are pretty good that if you’ve had your laptop for any length of time, dust has accumulated inside and has negatively affected the heatsink’s ability to remove heat from the CPU.
In preparation for removing the fan from the laptop, I downloaded a PDF of HP nx6110 service manual from the HP website. You can do a Google search for your laptop’s model and the words, ‘service manual’ to see if the manufacturer makes the service manual available online. You may notice that removing the fan seems to require all kinds of parts to be taken off the laptop since they seem to cover everything else first, but in my case, it only involved removing the keyboard, which turned out to be quite easy.
The steps were:
1. Remove battery and the cover for the memory (1 Phillips screw).
2. Remove 2 T8 Torx screws exposed after the memory cover is removed. These screws hold in the keyboard.
3. Slide four latches on the keyboard downward to release the keyboard.
4. Remove the fan (2 Phillips screws).
Although I removed the fan and keyboard cables, I found out later that I really didn’t need to do this to get at the heatsink, you can simply lay them over as long as you’re careful not to move them and put strain on the cables.
I’ve attached some images of the fan and heatsink below. Click on any image for a higher resolution version of it.
As you can see from the picture above, the fan is exposed once the keyboard is removed. It doesn’t appear to be too dirty, but the dust is hidden between the fan and the heatsink.
Now that the fan has been removed, you can see that there is a lot of dust that has accumulated on the heatsink. You can use a brush to remove the dust and then blow it out with compressed air.
The dust that had accumulated on the heatsink caused the air to be blocked and so the air that does get through is very hot since a smaller portion of the heatsink is being used to remove the heat. It can also increase the velocity of the air because it’s forced through a smaller restriction. Eventually, however, if it’s not cleaned, the heatsink will no longer be able to do its job at all and the computer could shut down due to overheating.
Once the heatsink was cleaned, the air that exited the vent was much cooler, and the fan didn’t need to work as hard to keep the CPU cool (around 45 °C). In doing some research, I found that the BIOS was using various CPU temperature thresholds to determine when to turn the fan on and when to increase its speed. In my case, the BIOS was original and it was turning the fan on at 40 °C, and so I decided to see if any improvements were possible by updating the BIOS. Sure enough, a newer BIOS available from HP’s website had raised this limit to 45 °C which turned out to be much better, since that is the temperature where the CPU tends to stabilize when it’s at idle and so the fan stays off unless you’re doing something that causes the CPU to become busy.
I have a friend with an HP laptop dv6 model and it had an overheating problem that was so severe that it would reach 90 °C and shut itself down whenever she used it for more than 15 minutes. After searching through forums for many weeks she finally came across a thread that suggested updating the video driver and the BIOS to fix an overheating issue. That turned out to be the fix in her case. Now her computer runs very cool. So make sure you’re running all the latest updates from the manufacturer.
If you clean your heatsink and your overheating problems persist, you may want to check and see if there are any processes that are keeping the CPU busy all the time. Any time the CPU utilization goes up, the fan will come on at a higher speed. You can use Windows built-in Task Manager to do monitor CPU utilization by pressing CTL-ALT-DEL keys simultaneously. A better solution than Task Manager for examining CPU utilization is the Process Explorer which is free for downloading from Microsoft. I also downloaded a free utility to monitor the CPU temperature called Core Temp. I found that I had multiple virus scanners running (you only need one of these) and some other processes I didn’t need, so I removed the software responsible for running these processes.
I found that although Core Temp was helpful, it sometimes interfered with the BIOS in reading the temperature of the CPU. A better program for measuring CPU temperature on this model of laptop was Speedfan.
If taking your computer apart sounds frightening to you, or if you have a laptop where absolutely everything must be removed to get to the heatsink, then another option is to use a can of compressed air that you can buy at any office store and blow air backward through the fan’s vent. Feel for which direction the fan blows and determine where it’s exhausting the warm air. Then shut down the computer and aim the straw into the exhaust vents and if you see dust coming out through the intake vents, then you’re making progress. When dust collects on the heatsink, it continues to attract more dust like a log jam in a river. Blowing the air backward through the vent can clear this log jam.
Posted on May 21st, 2012 1 comment
A few months ago, my friend Don showed me a picture he had of himself as a young boy along with his younger sister and older brother. Don will turn 80 this year and it appears he was about 5 in the photo, so it was about 75 years old. The photo had some damage from creases, missing areas, and a few dark spots and he wanted to get it restored but didn’t want to let go of the original since it was irreplaceable. He had an photo scanner sitting next to his computer, so I scanned in the original and emailed it to Jay Yozviak at Photography by Jay, who is the premier photographer in Northeastern Pennsylvania. I figured he’d know of a reliable service where the photo could be sent and restored to remove the defects it had accumulated over its 75 year life. You can see an image of the original photo here (you can click on images for higher resolutions versions of them):
I know that Jay is very capable with PhotoShop but didn’t realize that he also does photo restoration as part of his photography business. In a few days, Jay had restored the image and sent back the results. My friend was extremely pleased with how it turned out. As you can see below, the defects are gone.
He also made up a framed version of the image in black-and-white:
If you’d like to get a quote on getting your irreplaceable photos restored to their original condition, you can contact Jay at:
Photography by JAY
284 Dennison Street
Swoyersville, PA 18704
If you’re curious how photo restoration is done, here’s a time-lapsed video of someone doing it on YouTube. The video is only a few minutes, but it shows about 6 hours of work:


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10 Misconceptions of Hormone Replacement Therapy
In the ten years I worked at Quality of Life Medicine in Northern California, I educated every patient about how Hormone Replacement Therapy (HRT) works, what types of HRT was available, what the risks where for each type, what they could expect from the type of HRT they chose, and what their role was in successful hormone balancing. HRT is not for everybody but it can be life changing for a lot of miserable women if done correctly. Women don’t know they have a choice in HRT; some hormones are good, and others not so good. In fact, most doctors don’t know there are HRT options, and one of the biggest problems women face is finding a doctor with formal training in cyclic hormone restoration and a successful patient base. They don’t teach hormone restoration in medical school. Doctors learn what menopause is, and are instructed to manage the symptoms of it with low, static dose, synthetic hormones and/or toxic prescription drugs. Hormones don’t work like that so why is that the HRT standard of care?
Before a patient started any type of HRT in our practice, my job was to let them know what they can expect from each type of HRT so they could make an informed decision. This meeting took place over a two-hour period, and I also got to know the patient’s perspective on HRT. Patients were also generously forthcoming about what their primary care provider thought about HRT. I shook my head in disbelief that doctors are being so bold as to offer their strong opinion about HRT when they have no education, clinical training, or patients they’re successfully treating. It’s confusing for patients because they assume their doctor is educated in such things so when a doctor makes a blanket statement, the patient believes them.
Below is a list of the most common misconceptions about HRT based off roughly 4000 female patients:
1. Hormones Cause Cancer
If this were true, we’d all be dead. Synthetic hormones cause cancer, bioidentical hormones do not. You are at greater risk for cancer if your estrogen is in the tank. Estrogen is especially designed to protect a woman’s body from the degenerative diseases of aging, including cancer.
2. There is Only One Kind of HRT
There a couple ways to treat hormone deficiencies; treat the symptoms with a synthetic or natural low, static dose, or restore natural hormones to optimal levels, dosed in a cyclical manner that mimics a woman’s natural cycle.
3. Hormones Are for Old Women
There is a huge misconception that we get our hormones at puberty, and we all produce enough. PMS, perimenopause, and menopause are a direct result of estrogen deficiency, and can happen at any age.
4. Too Old for Hormones
Many women think once they’ve “passed” the “change”, they don’t need hormones. When women say this, it tells me how much they don’t know about HRT and the benefits of replacing the hormones that give life. Women feel much better on the right kind of HRT. With the right amount of estrogen, a woman can rebuild her bones, decreasing her risk, or reversing osteoporosis.
5. Doctors Know How to Prescribe HRT
Make sure before taking hormones to ask your provider where they received their hormone training. Your doctor may have a strong opinion about hormones but are not forthcoming with their lack of knowledge in this area, and can make a mess of the patient. It’s okay to ask your doctor about their training and the focus of their practice. It’s your body and your life. Hormones regulate everything in the human body, and you have a right to proper HRT.
6. Lowest Dose is Best
With the lack of knowledge and training in HRT, doctors are telling their patients the lowest dose is best for hormones. This is so far from the truth. This method is taught in medical school with the mindset of estrogen causes cancer so give the lowest dose for the shortest amount of time. Hormones need to be restored to levels that mimic a healthy woman, not an unhealthy woman. The goal is to fix the cause of hormone deficiency by naturally restoring hormones instead of treating the symptoms of hormone deficiency with a low dose.
7. Use Only for the Shortest Amount of Time
Uneducated doctors suggest this because they’ve been lied to that hormones cause cancer. If a woman’s hormones are balanced correctly, she will want to be on them as long as she can. Staying on them as long as she can will help her fight and reverse the degenerative diseases of aging, and make her feel good.
8. Use the Same Dose Everyday
This is a one-size-fits all mentality. I still haven’t come across a woman who has by exact physical issues or body. Every woman’s body works a little differently but one thing remains consistent if a woman is hormonally healthy and that is women’s bodies cycle with the phases of the moon (men’s bodies cycle with the solar system) and so does her hormones. On day six of a woman’s cycle, her estrogen begins an incline and peaks on day 12 (full moon), then falls to a low by day 18. Estrogen makes another incline peak at day 21 and drops again so a woman can shed her lining. Why give the same dose everyday if our bodies don’t function that way. One cannot have proper HRT if the hormones are not cycled and optimized.
9. HRT is a One-Size-Fits-All Regimen
No two women are the same. Uneducated doctors read the hormone sample insert in the box on how to dose the hormone, slap a patch on the patient, and call it HRT. Proper hormone restoration involves dosing the patient based on her body size, body type, level of deficiency, and how long they’ve been deficient. These are very critical elements in dosing. I tell my patients the regimen that works for me, wouldn’t work for them, and their HRT would do me any good. My body is very sensitive to testosterone so I take about a tenth less than a woman with average tolerance.
10. HRT is Quick and Simple
The last thing proper HRT is: quick and simple. Patients who are looking for a quick fix get terribly disappointed. Proper HRT is not conventional medicine. Every patient is different and needs to be dosed and treated as such. Proper HRT is a process over a period of time. The first month a patient is on the correct hormone protocol, they feel better but they’re skeptical about why they feel better. The second month is better than the first month because estrogen receptors are waking up, and can receive and utilize the estrogen. Each month more estrogen receptor sites are awakened, making the patient feel better and better, for some women up to a year.
If you have any questions, or would like me to expand further on a particular topic, feel free to mail me directly at [email protected], or leave a comment.

domain: medical


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I have said a lot of things about Taylor Swift that frankly, are not very nice. I’ve made fun of her sophomoric songs, her overacting at award ceremonies and even her flat live singing voice. I’m sorry I was so hard on her.
What brings about the change? Last nights Grammys. What a weird and wicked pile of dung. Usually, one of the few award shows I like, this was painful to watch. I guess I’m just getting old and turning into a curmudgeon.
Sure, there were some high points – Austin’s own, Gary Clark Jr did a great job. It was good to see Willie Nelson, Kris Kristofferson, Paul McCartney, Stevie Wonder, Ringo Starr and Merle Haggard still out there (although they all looked VERY tired.) Daft Punk was fun and P!nk continued to show how much more talented she is than most of the first ten rows of “stars.” I even enjoyed Pharrell’s freaky pick-a-nic basket ranger hat.
Lorde (Royals) was downright spooky and Kacey Musgraves (Follow Your Arrow) continues the decline of country music.
The entire show seemed more a political message than a celebration of music.
So what of Taylor Swift? For the first time since she burst onto the scene, Taylor won nothing! So what?
Well, I fear this may be a turning point for her. I hope that she will do the right thing and resist the call to “go nasty” as so many female artists do when record sales slip. She has enough money to last several lifetimes, but this fame creature is a mean one.
I regret the position that celebrity puts you in – when you win, you are a “spoiled brat” and “rich kid” When you lose, you are a “has been” and “washed up.” I wish her the best as she transitions to the next phase in her life and hope that she does so gracefully. I hope she makes the music her heart calls her to make and that the reaction of the public plays no role in how she feels about it.

domain: artistic


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Keiko Honda, executive vice president and CEO of the Multilateral Investment Guarantee Agency (MIGA) – the political risk insurance arm of the World Bank Group – is in Johannesburg this week to meet with private sector investors and government officials.
While in South Africa, Honda will take stock of progress on MIGA-backed projects, and explore opportunities for supporting further private sector activity.
“The Government has set an ambitious plan for drawing in private sector investment.
“We are committed to supporting this ambition by helping reduce risk for investors and lenders,” Honda said.
The guarantee agency said in a statement that it currently supports eight projects in South Africa, amounting to some $1.56 billion in political risk insurance and credit enhancement.
MIGA also provides guarantees amounting to over $630 million for outward investment from South Africa to other parts of Africa. MIGA’s current support to the continent as a whole is $4.9 billion.
Recent projects MIGA has supported in South Africa include three wind power farms to be built and run by Lekela Power in Khobab, Loeriesfontein, and Noupoort. Once operational, these farms will have a generation capacity of 360MW. Read more: Fact file: Northern Cape wind farms
In addition, MIGA has also recently supported first-time investments by CIGenCo SA in two solar power plants in neighbouring Namibia.
As a member of the World Bank Group, the agency is focused on development impact by helping mobilise private capital.
Clients with whom MIGA works in the country are expected to provide over 57,000 people with access to power, generate $546 million annually in government revenues, provide $1.6 billion in loans per annum, and avoid 1.4 million metric tonnes of greenhouse gases.


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Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin’s lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with HLA-B* 08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in Caucasians most likely represents a true etiologic factor remains uncertain. We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. SNPs in LTA and TNF and in six other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A) and rs6467 (C)) were associated with AIDS-NHL (OR=2.7, 95% CI: 1.5–4.8, p=0.0009 and OR=3.2, 95% CI: 1.6–6.6 p=0.0008; respectively). These two haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
lymphoma; B cell; cytokines; AIDS; immune activation
Currently, few rodent models of AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) exist. In these studies, a novel mouse/human xenograft model of AIDS-associated Burkitt lymphoma (AIDS-BL) was created by injecting cells of the human AIDS-BL cell line, 2F7, intraperitoneally into NOD-SCID mice. Mice developed tumors in the peritoneal cavity, with metastases to the spleen, thymus, and mesenteric lymph nodes. Expression of the chemokine receptor, CXCR5, was greatly elevated in vivo on BL tumor cells in this model, as shown by flow cytometry. CXCL13 is the ligand for CXCR5, and serum and ascites levels of murine, but not human, CXCL13 showed a striking elevation in tumor-bearing mice, with levels as high as 200,000 pg/ml in ascites, as measured by ELISA. As shown by immunohistochemistry, murine CXCL13 was associated with macrophage-like tumor-infiltrating cells that appeared to be histiocytes. Blocking CXCR5 on 2F7 cells with neutralizing antibodies prior to injection into the mice substantially delayed tumor formation. The marked elevations in tumor cell CXCR5 expression and in murine CXCL13 levels seen in the model may potentially identify an important link between tumor-interacting histiocytes and tumor cells in AIDS-BL. These results also identify CXCL13 as a potential biomarker for this disease, which is consistent with previous studies showing that serum levels of CXCL13 were elevated in human subjects who developed AIDS-lymphoma. This mouse model may be useful for future studies on the interactions of the innate immune system and AIDS-BL tumor cells, as well as for the assessment of potential tumor biomarkers for this disease.
The DNA-modifying processes that are involved in B lymphocyte activation, somatic hypermutation (SHM) and IgH class switch recombination (CSR), have the potential to lead to genetic errors that lead to the genesis of B cell cancers, such as lymphoma. Given the potential contribution of these immune mechanisms to the development of cancer, assessment of the expression of cytokines and other immune stimulatory molecules that drive B cell activation, prior to lymphoma diagnosis, may provide insights into the etiology of these cancers. Here, we review studies that have examined pre-diagnosis protein biomarkers for non-Hodgkin lymphoma (NHL), both AIDS-related NHL, as well as NHL seen in immunocompetent populations. Overall, these studies provide support for the notion that B cell hyper-activation is elevated preceding the appearance of AIDS-NHL, particularly those forms of AIDS-NHL that are not driven by EBV infection, and which presumably arise from errors in IgH CSR and SHM. In more limited studies, it appears that dysregulation of cytokine production also precedes the diagnosis of NHL in HIV-negative persons. The availability of pre-diagnosis serum/plasma from cohort studies provides unique opportunities for proteomic approaches to identify novel pre-diagnosis etiologic biomarkers for NHL.
Background. The homeostatic chemokine, CXCL13 (BLC, BCA-1), helps direct the recirculation of mature, resting B cells, which express its receptor, CXCR5. CXCL13/CXCR5 are expressed, and may play a role, in some non-AIDS-associated B cell tumors. Objective. To determine if CXCL13/CXCR5 are associated with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Methods. Serum CXCL13 levels were measured by ELISA in 46 subjects who developed AIDS-NHL in the Multicenter AIDS Cohort Study and in controls. The expression or function of CXCL13 and CXCR5 was examined on primary AIDS-NHL specimens or AIDS-NHL cell lines. Results. Serum CXCL13 levels were significantly elevated in the AIDS-NHL group compared to controls. All primary AIDS-NHL specimens showed CXCR5 expression and most also showed CXCL13 expression. AIDS-NHL cell lines expressed CXCR5 and showed chemotaxis towards CXCL13. Conclusions. CXCL13/CXCR5 are expressed in AIDS-NHL and could potentially be involved in its biology. CXCL13 may have potential as a biomarker for AIDS-NHL.
Up-regulation of heat shock protein 70 (HSP70) could be elicited primarily by heat in former studies, and this was proved to be associated with cancer progression. Burkitt's lymphoma is one of highly aggressive B-cell non-Hodgkin’s lymphoma and is one of the fastest growing human tumors. To investigate the effect of HSP70 expression on the sensitivity of human Burkitt lymphoma cells (Raji cells) to chemotherapy and its role in the involvement of PI3K/AKT pathway, we evaluated the effects of LY294002, a PI3K inhibitor, on the expression of HSP70 and cell sensitivity to adriamycin (ADM) or cisplatin (DDP). In present study, expressions of HSP70, AKT and phosphorylated AKT (p-AKT) in Raji cells were measured by Western-Blot. Apoptosis index of Raji cells was examined by flow cytometry. Cytotoxicities of adriamycin (ADM) and cisplatin (DDP) were determined by WST-8 assay. We found that hyperthermia (42 degrees for 1 hour) up-regulated the expression of HSP70 expression and blockade of PI3K/AKT pathway down-regulated HSP70 expression in Raji cells. Compared to cells treated with ADM or DDP alone, hyperthermia protected cells from chemotherapy while LY294002 enhanced sensitivity of Raji cells to chemotherapy. Our results suggested down-regulation of HSP70 expression by blockade of PI3K/AKT pathway maybe responsible for the increased sensitivity of Raji cells to chemotherapy. Targeting PI3K/AKT pathway or inhibiting HSP70 expression may be beneficial for chemotherapy treatment of Burkitt lymphoma patients.
Raji; Hyperthermia; HSP70; PI3K/AKT
Purpose of review
To estimate the impact of highly effective antiretroviral therapy (ART) on the incidence and prognosis of Hodgkin lymphoma among people with human immunodeficiency virus infection or AIDS (PWHA).
Age-adjusted incidence of Hodgkin lymphoma in PWHA is unchanged and is still five-fold to fifteen-fold higher than in the general population. Aging of the PWHA population with ART may account for increasing numbers of Hodgkin lymphoma cases. CD4 cell count has a complex relationship to Hodgkin lymphoma risk in PWHA. Depending on the time of measurement, Hodgkin lymphoma risk is highest with 50–249 CD4cells/µl, and falling CD4 count on ART may be a harbinger of Hodgkin lymphoma onset. HIV load appears irrelevant to Hodgkin lymphoma. For obscure reasons, Hodgkin lymphoma risk may be elevated soon after starting ART, but the risk is probably modestly reduced with 6 or more months on ART. For PWHA who develop Hodgkin lymphoma, ART and ABVD chemotherapy can be administered safely, with one recent study demonstrating equivalent outcomes for HIV-positive and HIV-negative Hodgkin lymphoma patients.
Vigilance for Hodgkin lymphoma is needed for immune-deficient PWHA, including those on ART. ART with opportunistic infection prophylaxis enables the delivery of effective chemotherapy for Hodgkin lymphoma, leading to a good prognosis.
acquired immunodeficiency syndrome; antiretroviral therapy; cancer chemotherapy; CD4 count; Hodgkin lymphoma; human immunodeficiency virus
Patients with autoimmune disorders seem to have an elevated risk of lymphoma, especially non-Hodgkin’s lymphoma (NHL). The increased risk has been attributed to the disturbance of immune function found in these patients or to the immunosuppressive therapy used to treat the autoimmune disorders. However, little information exists about the estimated baseline risk for lymphoma in patients with primary biliary cirrhosis (PBC). In this case report, we describe a female patient who developed nodal diffuse large B-cell lymphoma ten years following PBC diagnosis. Twenty five additional case reports (19 NHL and 4 Hodgkin’s disease (HD), 2 without data about NHL or Hodgkin’s disease) predominantly females were identified in the English literature. B-cell lymphoma was the most common NHL type reported but beyond that no clear predisposition for any specific lymphoma subtype was documented. PBC usually preceded lymphoma diagnosis. Fifteen cases had extranodal localization and the most common site was the liver.
PBC; non-Hodgkin’s lymphoma; autoimmune disorders
Genetic variations in human leukocyte antigens (HLA) are critical in host responses to infections, transplantation, and immunological diseases. We previously identified associations with non-Hodgkin lymphoma (NHL) and the HLA-DRB1*01:01 allele and extended ancestral haplotype (AH) 8.1 (HLA-A*01-B*08-DR*03-TNF-308A). To illuminate how HLA alleles and haplotypes may influence NHL etiology, we examined potential interactions between HLA-DRB1*01:01 and AH 8.1, and a wide range of NHL risk factors among 685 NHL cases and 646 controls from a United States population-based case-control study. We calculated odds ratios and 95% confidence intervals by HLA allele or haplotype status, adjusted for sex, age, race and study center for NHL and two major subtypes using polychotomous unconditional logistic regression models. The previously reported elevation in NHL risk associated with exposures to termite treatment and polychlorinated biphenyls were restricted to individuals who did not possess HLA-DRB1*01:01. Previous associations for NHL and DLBCL with decreased sun exposure, higher BMI, and autoimmune conditions were statistically significant only among those with AH 8.1, and null among those without AH 8.1. Our results suggest that NHL risk factors vary in their association based on HLA-DRB1*01:01 and AH 8.1 status. Our results further suggest that certain NHL risk factors may act through a common mechanism to alter NHL risk. Finally, control participants with either HLA-DRB1*01:01 or AH 8.1 reported having a family history of NHL twice as likely as those who did not have either allele or haplotype, providing the first empirical evidence that HLA associations may explain some of the well-established relationship between family history and NHL risk.
HIV-infected persons have an elevated risk of developing non-Hodgkin's lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals.
Patients and Methods
By using three cohorts of HIV-infected persons (from 1982 to 2005), we identified 66 individuals who developed NHL and 225 matched (by cohort, sex, ethnicity, age, and CD4 count), HIV-infected, lymphoma-free controls who had available stored prediagnostic blood samples. Serum/plasma samples obtained 0 to 2 years and 2 to 5 years before diagnosis/selection were assayed for IgG, IgM, and IgA levels; monoclonal (M) Igs; and κ and λ free light chain (FLC) levels. Patients and matched controls were compared by using conditional logistic regression.
The κ and λ FLCs were both significantly higher in patients (eg, in 2- to 5-year window: median κ, 4.24 v 3.43 mg/dL; median λ, 4.04 v 3.09 mg/dL) and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection (eg, NHL risk 3.76-fold higher with κ concentration at least 2.00 times the upper limit of normal, and 8.13-fold higher with λ concentration at least 2.00 times the upper limit of normal compared with normal levels). In contrast, IgG, IgM, and IgA levels were similar in patients and controls. M proteins were detected in only two patients with NHL (3%) and in nine controls (4%), and they were not significantly associated with NHL risk.
Elevated FLCs may represent sensitive markers of polyclonal B-cell activation and dysfunction and could be useful for identifying HIV-infected persons at increased NHL risk.
B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes.
Non-Hodgkin and Hodgkin lymphomas frequently involve many structures in the abdomen and pelvis. Extranodal disease is more common with Non-Hodgkin's lymphoma than with Hodgkin's lymphoma. Though it may be part of a systemic lymphoma, single onset of nodal lymphoma is not rare. Extranodal lymphoma has been described in virtually every organ and tissue. In decreasing order of frequency, the spleen, liver, gastrointestinal tract, pancreas, abdominal wall, genitourinary tract, adrenal, peritoneal cavity, and biliary tract are involved. The purpose of this review is to discuss and illustrate the spectrum of appearances of nodal and extranodal lymphomas, including AIDS-related lymphomas, in the abdominopelvic region using a multimodality approach, especially cross-sectional imaging techniques. The most common radiologic patterns of involvement are illustrated. Familiarity with the imaging manifestations that are diagnostically specific for lymphoma is important because imaging plays an important role in the noninvasive management of disease.
The clinical utility for establishing the immune phenotype in patients with non-Hodgkin's lymphoma is controversial. To help resolve this dilemma, we studied 104 consecutive patients with diffuse large cell lymphoma, the most common subtype of potentially curable non-Hodgkin's lymphomas. The presence or absence of the human class II histocompatibility antigen was determined using the monoclonal antibody anti-HLA-DR (Ia), and the results correlated with pretreatment clinical features and survival. We found that eight HLA-DR negative patients had similar pretreatment clinical characteristics compared with 96 HLA-DR positive patients, but HLA-DR negative patients had a significantly shorter survival duration compared with HLA-DR positive patients (P = 0.003 log-rank). The median survival of the HLA-DR negative patients was 0.5 years compared to 2.8 yr for the HLA-DR positive patients. No HLA-DR negative patient survived beyond 1.5 yr. A multi-variate analysis, adjusting for prognostic factors of known clinical significance, confirmed the importance of HLA-DR as a prognostic factor (P = 0.016). We conclude that determining the presence of HLA-DR is a relatively simple pretreatment study that identifies a small but important group of patients who are not curable using currently available combination chemotherapy.
Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins which play an essential role as molecular chaperones in protein folding and transport. Heat Shock Protein 90 (Hsp90) is not mandatory for the biogenesis of most proteins, rather it participate in structural maturation and conformational regulation of a number of signaling molecules and transcription factors. Hsp90 has been shown to play an important role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Dysregulated expression of Type I interferon α, activation of B cells and production of autoantibodies are hallmarks of SLE. The enhanced levels of Hsp90 were detected in the serum of SLE patients. The elevated level of Hsp90 in SLE has also been correlated with increased levels of IL-6 and presence of autoantibodies to Hsp90. This suggests that Hsp90 may contribute to the inflammation and disease progression and that targeting of Hsp 90 expression may be a potential treatment of SLE. The pharmacologic inhibition of Hsp90 was successfully applied in mouse models of autoimmune encephalomyelitis and SLE—like autoimmune diseases. Thus targeting Hsp90 may be an effective treatment for SLE, especially if combined with other targeted therapeutic approaches.
Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation.
This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays.
A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers.
These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.
A chimeric HLA-DR4-H2-E (DR4) homozygous transgenic mouse line spontaneously develops diverse hematological malignancies with high frequency (70%). The majority of malignancies were distributed equally between T and B cell neoplasms and included lymphoblastic T cell lymphoma (LTCL), lymphoblastic B cell lymphoma (LBCL), diffuse large B cell lymphoma (DLBCL), the histiocyte/T cell rich variant of DLBCL (DLBCL-HA/T cell rich DLBCL), splenic marginal zone lymphoma (SMZL), follicular B cell lymphoma (FBL) and plasmacytoma (PCT). Most of these neoplasms were highly similar to human diseases. Also, some non-lymphoid malignancies such as acute myeloid leukemia (AML) and histiocytic sarcoma were found. Interestingly, composite lymphomas, including Hodgkin-like lymphomas, were also detected that had CD30+ Hodgkin/Reed-Sternberg (H/RS)-like cells, representing a tumor type not previously described in mice. Analysis of microdissected H/RS-like cells revealed their origin as germinal center B cells bearing somatic hypermutations and, in some instances, crippled mutations, as described for human Hodgkin lymphoma (HL). Transgene integration in an oncogene was excluded as an exclusive driving force of tumorigenesis and age-related lymphoma development suggests a multi-step process. Thus, this DR4 line is a useful model to investigate common molecular mechanisms that may contribute to important neoplastic diseases in man.
The goal of this editorial is to revisit soluble human leukocyte antigens (sHLA) and to highlight the findings reported by Albitar et al. in this issue on the relation between sHLA levels in Non-Hodgkin’s Lymphoma (NHL) and Hodgkin’s Disease (HD). We will review key aspects of sHLA including soluble HLA-G, which has received a lot of attention in recent publications. We will then address the role of sHLA in lymphoproliferative diseases and in solid organ tumors. Lastly, we will comment on the results of Albitar et al. and their relevance to clinical application in NHL.
soluble human leukocyte antigen; non-Hodgkin’s Lymphoma; graft monitoring; immune modulation
Heat shock proteins (Hsps) are ubiquitous proteins that are induced following exposure to sublethal heat shock, are highly conserved during evolution, and protect cells from damage through their function as molecular chaperones. Some cancers demonstrate elevated levels of Hsp70, and their expression has been associated with cell proliferation, disease prognosis, and resistance to chemotherapy. In this study, we developed a tetracycline-regulated gene expression system to determine the specific effects of inducible Hsp70 on cell growth and protection against hyperthermia in MCF-7 breast cancer cells. MCF-7 cells expressing high levels of Hsp70 demonstrated a significantly faster doubling time (39 hours) compared with nonoverexpressing control cells (54 hours). The effect of elevated Hsp70 on cell proliferation was characterized further by 5-bromo-2′deoxyuridine labeling, which demonstrated a higher number of second and third division metaphases in cells at 42 and 69 hours, respectively. Estimates based on cell cycle analysis and mean doubling time indicated that Hsp70 may be exerting its growth-stimulating effect on MCF-7 cells primarily by shortening of the G0/G1 and S phases of the cell cycle. In addition to the effects on cell growth, we found that elevated levels of Hsp70 were sufficient to confer a significant level of protection against heat in MCF-7 cells. The results of this study support existing evidence linking Hsp70 expression with cell growth and cytoprotection in human cancer cells.
An 8-yr-old nonallergic girl with non-Hodgkin's lymphoma had markedly elevated serum IgE at presentation (greater than 10,000 IU/ml), negative skin tests to a battery of 24 common allergens, and no evidence of parasitic infestation. Serum levels of IgG, IgA, and IgM were normal. Remission after cytotoxic chemotherapy was accompanied by a marked reduction in serum IgE levels (to less than 200 IU/ml) with no change in the level of serum IgG, IgM, or IgA. Recurrence of the lymphoma 7 mo after remission was accompanied by an isotype specific rise in serum IgE (to 3,850 IU/ml). Isoelectric focusing revealed that the IgE was polyclonal. Phenotypic analysis of the lymphoma obtained during relapse revealed all (greater than 98%) cells to be T3+, T4+, and T8+. Incubation of lymphoma cells with human myeloma IgE followed by immunosorbent purified fluorescein tagged goat anti-human IgE (anti-IgE PS-adsorbed over IgE ADZ) stained 25% of the cells. In contrast, less than 1% of the cells were stained after incubation with human IgG followed by fluorescein conjugated goat anti-human IgE. Supernatants from lymphoma cells (5 X 10(6)/ml, 48 h) enhanced IgE production in B cells derived from four patients with allergic rhinitis (mean +/- SD picograms per milliliter of net IgE 930 +/- 320 in unstimulated cultures versus 2,450 +/- 650 in cultures stimulated with lymphoma supernatants; P less than 0.01) but did not induce IgE synthesis in B cells from two normal subjects that synthesized no IgE spontaneously. Lymphoma supernatants failed to enhance IgG synthesis by B cells of both allergic and nonallergic subjects. These results indicate that a T cell lymphoma comprised of cells bearing Fc receptors for IgE with a phenotype characteristic of immature T cells (i.e., T3+, T4+, T8+) exhibited IgE specific helper function. This lymphoma may represent the monoclonal expansion of a subpopulation of IgE specific helper T cells.
Objective: Multidrug resistance is a cause of treatment failure in patients with malignant lymphoma; however, the frequency and clinical relevance of multidrug resistance protein expression are unclear. The present study aimed to investigate expression of the most common multidrug resistance proteins in a group of lymphoma patients.
Material and Methods: The study included 44 previously untreated lymphoma patients (non-Hodgkin’s lymphoma [n = 21], non-malignant lymphadenopathy [n = 13], and Hodgkin’s lymphoma [n = 10]). MDR1, MRP, and LRP expression was assessed via quantitative PCR of lymph node biopsy specimens.
Results: In the non-Hodgkin’s lymphoma group MDR1 was positive in 23.8% (5/21) of the patients, MRP was positive in 57.14% (12/21), and LRP was positive in 90.47% (19/21). In the non-malignant lymphadenopathy group, MDR1 was positive in 46.15% (6/13) of the patients, MRP was positive in 84.61% (11/13), and LRP was positive in 100% (13/13). In the Hodgkin’s lymphoma group MDR1 was positive in 50% (5/10) of the patients, MRP was positive in 50% (5/10), and LRP was positive in 80% (8/10). MDR1, MRP, and LRP expression did not differ between the 3 groups. Furthermore, MDR1, MRP, and LRP expression wasn’t associated with tumor stage, response to first-line therapy, the erythrocyte sedimentation rate, or C reactive protein, beta 2 microglobulin, serum lactate dehydrogenase, and albumin levels. Additionally, survival time in the MDR1- and MRP-positive, and MDR1- and MRP-negative patients did not differ (comparison of LRP was not possible due to the small number of LRP-negative patients).
Conclusion: According to the present findings, future studies should investigate alternative pathways of multidrug resistance in order to arrive at a better understanding of treatment failure in lymphoma patients.
Multidrug resistance; non-Hodgkin’s lymphoma; Hodgkin’s lymphoma; Survival
There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.
The heat shock response is among the most highly conserved examples of regulated gene expression, being present in all cellular organisms. Transcriptional activation of heat shock genes by increased temperature or other cellular stresses is mediated by the binding of a heat shock factor (HSF) to a conserved nucleotide sequence (the heat shock element) present in the promoter of heat-inducible genes. Despite the high degree of conservation of this response, embryonic stages of development are characterized by the absence of a heat shock response. Murine erythroleukemia (MEL) cells also lack this response, and we report here a detailed characterization of this defect for one of the most highly conserved of these genes, hsp70. Surprisingly, heat-induced transcriptional activation of this gene does not occur, despite the induction of a protein with the binding specificity of murine HSF. However, the MEL HSF differs slightly in apparent size from the HSF in 3T3 cells, which exhibit a normal heat shock response. These data suggest that activation of mammalian HSF by heat requires at least two separate steps: an alteration of binding activity followed by further modification that activates transcription. MEL cells do not respond to heat shock because they lack the ability to perform this secondary modification. These cells provide a useful system for characterizing heat shock activation in mammals.
Angiogenic switch marks the beginning of tumor’s strategy to acquire independent blood supply. In some subtypes of non-Hodgkin’s lymphomas, higher local vascular endothelial growth factor (VEGF) expression correlates with increased microvessel density. However, this local VEGF expression is higher only in tumors with elevated expression of the receptors of the growth factor, suggesting an autocrine growth-promoting feedback loop. Several studies have indicated that VEGF receptors are also targeted by Tat protein from the HIV-1-infected cells. Given the similarity of the basic region of Tat to the angiogenic factors (basic fibroblast growth factor, VEGF), Tat mimics these proteins and binds to their receptors. We evaluated the role of HIV-1 Tat in regulating the level of VEGF expression and microvessel density in the AIDS-related diffuse large B-cell (DLBCL) and Burkitt lymphomas (BL). By luciferase assay, we showed that VEGF promoter activity was downregulated in vitro in cells transfected with Tat. Reduced VEGF protein expression in primary HIV-1 positive BL and DLBCL, compared to the negative cases, supported the findings of promoter downregulation from the cell lines. Microvascular density assessed by CD34 expression was, however, higher in HIV-1 positive than in HIV-1 negative tumors. These results suggest that Tat has a wider angiogenic role, besides the regulation of VEGF expression. Thus, targeting Tat protein itself and stabilizing transient silencing of VEGF expression or use of monoclonal antibodies against their receptors in the AIDS-associated tumors will open a window for future explorable pathways in the management of angiogenic phenotypes in the AIDS-associated non-Hodgkin’s lymphomas.
HIV-1 Tat; Microvessel density; Diffuse large B-cell; Burkitt lymphoma
Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9417-7) contains supplementary material, which is available to authorized users.
Heat shock proteins; HEAT shock factor 2; All-cause mortality
Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22–23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22–23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.
Key Words: lymphoid malignancy • mutation • ataxia telangiectasia gene


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By Daniel Sokatch, International CEO of the New Israel Fund
The new year has barely arrived, and already so much has happened.
On Tuesday the Jerusalem municipality evicted fifteen members of the Salhiye family from their house in the contested Sheikh Jarrah neighbourhood in the middle of a freezing Jerusalem night. They then immediately demolished their home. Fifteen more people are homeless in Sheikh Jarrah today than were at the start of the week, their home a pile of rubble. Our project partners and some staff were there, standing with the family, in the middle of the night, documenting this disgrace.
It’s also hard to believe that this past Saturday, I once again found myself praying for the safety of a rabbi and his congregants as a gunman took them hostage at a synagogue in Colleyville, Texas. I’m relieved that all four emerged physically unharmed, but I know that this attack leaves another Jewish community traumatized, and instills in all of us the fear that our synagogue might be next.
It has never been more clear that, wherever and whoever we are, our path to safety lies in solidarity with each other.
This path can be a tough one to walk. It requires the difficult work of building alliances, and coalitions and true partnerships – but this is the work that NIF was built for.
The new year has brought a breathtaking amount of news from Israel. And—as it always is for us—it’s everything at once: the good, the bad and the ugly.
The good was great. The Supreme Court ruled that Israel’s Interior Ministry that it could not continue prevent Palestinian couples—where one partner is from the West Bank and one is from Israel — from living together in Israel. The law that previously enabled the Ministry to do so expired last July. The Supreme Court’s ruling was a response to a petition by organizations funded by the NIF global network: the Association for Civil Rights in Israel (ACRI), Physicians for Human Rights Israel (PHRI) [NIFC project partners] and Hamoked: Center for the Defense of the Individual. We hope this will mean that families can live together again – that the norm will shift from the Ministry of the Interior denying petitions for family unification to a new normal of accepting them. Rest assured though: we and our partner organizations will be watching and monitoring the situation.
Some of the “bad” is painful to write about. Alongside evictions and demolitions in Sheikh Jarrah, over the last two weeks two elderly men died at the hands of the Israeli military. An 80-year-old Palestinian-American was beaten, handcuffed, and left at a construction site in the northern West Bank, and the beloved 75-year-old activist Haj Suleiman Hathaleen, who was run over by an Israeli military vehicle a few weeks ago, died in a Hebron hospital. These tragedies represent a grim reality of Israel’s 54-year-old occupation and settlement enterprise occupation for the millions of Palestinians who live under it.
NIF is dedicated to building a different reality and a better future for everyone.
Some of this work — work to stop displacement, to end home demolitions, and provide basic services to people who need them — is being done in Israel’s Negev right now by organizations funded by the NIF global network.
This is where the “ugly” comes in.
Ahead of the holiday of Tu B’shvat (also known as “the new year of the trees”), the Jewish National Fund – Keren Kayemeth Le’Yisrael (JNF-KKL) resumed a project (at the request of a government body — the Israel Lands Authority) to plant trees in and around Bedouin communities in the Negev. While planting trees sounds innocuous, the JNF project represents a decades-long effort to prevent Bedouin communities from expanding or obtaining legal recognition—and the basic services that come with it—under the pretext of making the desert bloom.
Shatil, NIF’s action arm, called the project “a political act aimed at constricting development and preventing recognition of Bedouin villages,” and said that “the planting is taking place on land where the government is working to dispossess the Bedouin; the goal of the planting is to encircle the Bedouin communities.” In large part as a result of these government policies, some 80% of Negev Bedouin live under the poverty line. Many live without running water or electricity because their villages are “unrecognized” by the state. It was with all of this in the background that local Bedouin residents began protesting the JNF project. The police and Shin Bet (Israel’s “General Security Service”) responded aggressively, arresting over 100 protesters (including minors) and injuring several others. It was truly ugly.
But, NIF has been working with these communities for years, and we are deeply invested in making sure all Israeli citizens — including, and perhaps especially, the Bedouin in the Negev — have access to all the services a country like Israel has to offer.
Of course, this is always true: we were dedicated to equal rights and access for all before the news of last week and we’ll be dedicated to it after the headlines fade. This time though, the story in the Negev turned into a national political fracas. Ra’am, the tiny conservative and religious Arab party in the governing coalition, draws nearly 80% of its constituency from the Negev Bedouin. Mansour Abbas, the party leader, decided his party would boycott Knesset votes until the JNF planting matter was settled. His decision to do so brought the coalition’s ability to function to a screeching halt– a moment that starkly reflected the historic political reality of this government: for the first time in Israeli history an Arab party in a ruling coalition cobbled together with a bare majority can, just like any other party, demand its interests be taken seriously. Ra’am is a power broker, not a token party.
Of course, NIF partners and our action arm, Shatil, were also working alongside the protesting Bedouin. Adalah — Legal Center for Arab Minority Rights in Israel together with Shatil released an open letter to the government, calling on Israel to halt the plantings, deescalate police involvement, disband and reallocate resources from the committee that oversees the planting, and move forward recognition of the Bedouin communities. Adalah is representing those who were arrested while protesting; NIF’s flagship project partner, the Association for Civil Rights in Israel (ACRI), is working to hold police accountable for violence against protestors. A number of other organizations funded by the NIF global network, including Bimkom — the Regional Council for Unrecognized Villages in the Negev [an NIFC project partner], and the Negev Coexistence Forum for Civil Equality, are working towards recognition for unrecognized Bedouin villages.
It is not lost on me that this Monday we marked Martin Luther King, Jr. Day. King implored us to not remain passive in the face of injustice and discrimination. In May 1958, he addressed the National Biennial Convention of the American Jewish Congress and told the story of the first Jews to arrive in the U.S. — refugees fleeing religious persecution in Europe. He noted that instead of leaving America in the face of discrimination, the Jewish immigrants “peacefully and in dignity asserted their moral and political right to remain to settle as equals and to contribute to the building of a new society.”
It is my hope for all of us and for those with whom our project partners work — whether its Palestinian families simply trying to live together, the now-evicted residents of Sheikh Jarrah, or the Bedouin in the Negev crying out for recognition – that this spirit of dignity and the assertion of moral and political rights guide us as we persist in our fight for a more just, equitable, and democratic society for all.

domain: sociology


Due to Covid-19 related issues affecting the entire world, KLM has longer than normal production times. Please plan for FORTY-FIVE plus working days for all custom and made-to-order products. These delays are due to raw material issues, supply chain disruptions, economic and the government policies we have no control over. We apologize in advance for these delays and ask that you plan accordingly.
EXPEDITED SERVICE: If you require replacement brake lines for your truck in a shorter time frame this is available when you choose an expedited freight service for delivery. Rush Services are available in relation to shipping times in transit only. This all relates back to Raw Material Shortages which have caused the production delays as this will not expedite order fulfillment times! when you choose either UPS or USPS Express Delivery Services.
NOTE:USPS Priority Mail Is Not An Express Service.
Replacement Braided Stainless Steel Kevlar Reinforced Brake Lines for the GMC Canyon pickup trucks.
These Kevlar Braided Stainless Steel Braided Brake Lines work on these GM models:
2016 GM Canyon 4WD models with Stabilitrak
2017 GM Canyon 4WD models with Stabilitrak
2018 GM Canyon 4WD models with Stabilitrak
2019 GM Canyon 4WD models with Stabilitrak
2020 TO 2021 GM Canyon 4WD Please call 203-210-7200
KLM Performance offers these custom-made replacements Braided Stainless Steel Brake Line Kits for your 2016 to 2019 GM Canyon as a Custom Made product to meet your exact requirements. These Stainless Steel Kevlar Reinforced Braided Stainless Steel brake line Kits are designed for the Four Wheel Drive models of GMC Canyon. The GM Canyon is an excellent compact pickup, but if you want to make it more reliable and stop quicker, consider improving parts like the brake lines.
NOTE:Please allow forty-five working days to manufacture your custom-made GMC Canyon Stainless Steel Brake Line Set. Make sure that you order the correct GM Canyon Series brake line length and color as these custom-made brake lines are Non-Returnable!
EXPEDITED ORDER PROCESSING
Is No Longer Available On Any Custom Made Brake Line Order Due To Raw Material Constraints, Current Economic Policies and the Lingering Effects Of The Covid-19 Virus Released Upon The World!
NOTE: USPS Priority Mail is not Expedited Shipping!
NOTES: This Canyon pickup braided stainless-steel brake line kits:
These KLM Performance Replacement Stainless Steel Braided Brake Lines for your 2016 to 2019 GM Canyon with the Stabilitrak Electronic Stability Control are sold as a four-piece set.
The 4 Piece Replacement Brake Line Kits include the two front caliper lines and two rear drop lines.
KLM Performance offers the two direct bolt-on rear caliper lines as an option for this stainless steel braided brake line kit. The Rear Caliper Lines purchase will now make your package a Six piece custom-made brake hose kit.
NOTE: These Custom Made replacement brake line kits are a NONRETURNABLE item. So please be sure you correctly order exactly the equipment you need for your General Motors Four Wheel Drive Canyon Series truck.
These 2016 to 2019 GM Canyon pickup custom made brake line kits are available in the following colors:
NOTE:KLM Performance Inc does not accept returns on these custom-made Replacement Brake Line Assemblies! Please make sure you order the correct Custom Made 2016 to 2019 GMC Canyon Four Wheel Drive model Replacement Brake Lines for your vehicle!
The benefits of installing a set of Replacement Brake Lines on your Canyon pickup truck are as follows:
Each replacement brake line kit includes all hardware required to fit your particular year, make, and model.
KLM Performance Brake Hose Assemblies are designed to meet the Federal MVSS-106 standard.
The D.O.T. approved Assemblies are constructed using 60-10997 Hose.
The 60-10997 Hose has virtually no volumetric expansion, so the brake response is immediate.
Brake pedal response is quick, not "soft" as with other standard hoses.
Reduces stopping distance
Virtually eliminates Anti-Lock Brake System pedal chatter.
Replacement Brake Line Assemblies comply with federal regulations D.O.T. MVSS-106.
All assemblies are pressure tested to 4500 PSI.
These Replacement Brake Lines are Legal for all street and racing vehicles.
KLM Performance brake lines offer better performance and higher safety.
2016 to 2019 GMC Canyon models with Stabilitrak Replacement Brake Lines assemblies are constructed to the following standards:
Rugged construction resists shock and road hazards.
Utilizing a Kevlar braided sheath over extruded Teflon tubing
Kevlar Braided Sheath is then protected with a five-layer stainless steel outer sleeve.
Abrasion and corrosion resistant to stay good looking for a long time to come
Assemblies using 60-10997 Hose. Virtually no volumetric expansion
Brake Hose Assemblies Designed To Meet MVSS-106 For D.O.T
Hose ends have a higher fitting pull-off rating than other D.O.T. assemblies.
Standard S.A.E. female fittings and new leader ends are available.
New stronger one-piece designed ends
Utilizes standard brake fitting adapters
Are direct bolt-on replacements of the O.E.M. rubber brake lines
Hose ends to match the O.E.M. fittings to ensure proper fit and easy installation.
All assemblies are pressure tested to 4500 PSI.
Legal for all street and racing vehicles
These features ensure that the GMC Canyon models with Stabilitrak Replacement Brake Lines are state of the art. These high performance Colorado two-wheel drive compact pickup truck replacement brake lines are state of the art and can be custom made to accommodate any lift kit or suspension system on the market. Have a question regarding replacement brake lines for your Chevy Colorado models with Stabilitrak or without Stabilitrak? Drop us a line at 203-210-7200 or contact us.
NOTE: BRAKES ARE A SAFETY-CRITICAL PART OF A MOTOR VEHICLE.
The Canyon replacement brake line components must be professionally installed by a competent mechanic. Any incorrect installation of brake components can cause a significant safety problem or an accident. If you are not a skilled and qualified mechanic, you should not attempt to install these replacement brake lines on your GM Canyon truck!
When you want your GMC Canyon to Stop Sooner, Decrease your stopping distance, or Slow Down Faster, use KLM Performance Canyon Stainless Steel Brake Lines to get the job done!
KLM PERFORMANCE 2016 to 2019 GMC Canyon4WD REPLACEMENT BRAKE LINES KITS ARE MADE IN THE USA
Engine:2.5L | 3.5L | 2.8L
Item Number: KLM GM C 16-19
Make GM - General Motors
Model: Canyon 4X4
Year: 2016 | 2017 | 2018 | 2019
Manufacturer Part No: KLM GM C 16-19
Product Application: 2016 to 2019 GM Canyon 4WD Models
Brand: KLM Performance
FAQ: What is the main reason to install Kevlar Reinforced Braide Stainless Steel brake Lines on my GMC Canyon Four-Wheel Drive truck? Kevlar Reinforced Five Layer Braided Stainless Steel Brake Lines do not expand. By eliminating the expansion the hydraulic pressure is instantly transferred to the brake calipers providing dramatically improved brake system response and shorter stopping distances.
Part Number: KLM GM C 16-19
Manufacturer: KLM Performance
Product Note: The installation of these Custom Made Kevlar Reinforced braided Stainless Steel Brake Lines provides a dramatic improvement in brake system performance and pedal feel.


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When it comes to decorating your home, it is necessary that you buy furniture pieces from the best home furniture stores in Abu Dhabi and use them in the most creative manner so that they can enhance the look and feel of your living environment.
You should also make sure that you choose furniture pieces that are in line with the nature of space that you have in your home.
While choosing furniture items for your home, you should try to strike a balance between functionality and aesthetics so that your living environment looks positively vibrant.
Here are some cool decoration tips and trends that you can try out for this year. The new decoration trends for 2018 presented here are recommended by Pure Italian, a leading furniture manufacturing company in UAE.
While plenty of people still love to stick with neutral shades when it comes to their interiors, more people would want to experiment with bolder shades this year.
A popular practice this year would be to combine dynamically colored furniture pieces with wall designs that further help in accentuating their beauty.
While many people will want to work with contrasting shades that can bring out the brightness of their wall paint in Dubai and furniture pieces, there will also be those who would love to have both their furniture and walls in equally vibrant shades.
Another trend that will be noticeable with increasing propensity this year would be to make use of moody interiors with the application of colors like brooding violet, emerald green and striking navy.
While home furniture in Abu Dhabi that are done in light shades of wood have enjoyed a consistent popularity for many years, we can expect a surge of interest among homeowners to invest in pieces that are made with various shades of dark wood.
The darker shades of wood can not only appeal to all those who share a strong penchant for retro looking furniture items, but they are also favored by everyone who wants to create a contrasting look with light shaded interiors and wall colors.
Makers of custom furniture in Abu Dhabi will likely get more orders that focus on using dark shades of wood such as parquet tiling in Abu Dhabi in a more creative manner.
More people this year will prefer to go for furniture pieces that come with a minimalistic design and are equipped with simple but effective glamour elements.
For instance, furniture pieces with metallic legs and handles are going to find an ever-increasing audience in the coming months. The reason for this is that they do offer the best finishing touches to any rustic looking furniture item.
Moreover, furniture pieces that combine gold, brass, walnut, black and marble will be able to appeal to buyers who prefer to invest in sophisticated furniture items.
High-street pieces and retro items like wishbone-style dining chairs will enjoy greater popularity due to their rich wood stains.
Furniture made with contemporary styled walnut wood samples can help to explore the natural grainy beauty of these wooden materials.
Pastel shades and ikat prints will be a popular trend when it comes to pillows and cushions used with the furniture pieces since they always carry a nice, positive vibe of their own.
Decorative cushions and covers in Abu Dhabi will be in, as more homeowners will experiment with beautifully styled products.


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The Adventure of Casino Site Online Gambling: Everything You Need to Know
In this post, we’ll take a more detailed look at casino mufasabet site online gambling, from its background, and also appeal to its downsides as well as benefits. Sit back, loosen up, and get prepared to find out everything you need to understand regarding gambling establishment online betting.
Discover the globe of online casino online gambling and experience the excitement of the video game from the convenience of your own residence. Find out about its background, appeal, advantages, as well as drawbacks in this insightful write-up.
Today, millions of people around the world delight in casino online betting, which enables them to play their favored video games from the convenience of their own houses. In this post, we’ll take a better look at the globe of casino sites and online betting and explore its many benefits as well as negative aspects.
What is Casino Site Online Gaming?
Gambling enterprise online betting is a kind of online mufasabet video gaming that allows players to bank on various casino sites games using the internet. These video games consist of timeless table games such as blackjack, baccarat, and live roulette, in addition to a variety of ports, video Texas hold ’em, and also various other preferred casino video games. Players can access these games using their tablets, computers, or smartphones and also play them for real cash or just for fun.
The Background of Online Casino Online Gambling
The history of casino online gaming can be mapped back to the mid-1990s when the initial online gambling establishments were developed. These early online casinos were primitive by today’s criteria, offering only a handful of video games and also standard graphics. Nonetheless, they swiftly expanded in popularity, and by the very early 2000s, there were dozens of online casinos available to players worldwide. Today, there are numerous online casino sites, each using a wide range of games and features developed to appeal to a wide target market.
Advantages of Gambling Enterprise Online Gambling
There are numerous advantages to gambling enterprise online gambling, consisting of:
One of the most considerable benefits of casino site online betting is the convenience it uses. Players can access their preferred gambling enterprise video games from anywhere at any moment, whether they’re at house, at the workplace, or on the go. This ease means that gamers can fit gambling into their active routines without having to sacrifice various other vital activities.
Selection of Games
An additional advantage of casino online betting is the wide array of games readily available. Unlike conventional casinos, which might be limited by room or other factors, online casinos can offer hundreds and even hundreds of various video games to players. This means that players can quickly find games that match their choices, whether they’re searching for timeless table video games, contemporary slots, or anything in between.
Incentives and Incentives
On the internet gambling enterprises also provide a wide variety of rewards as well as bonus offers to players, consisting of welcome rewards, deposit bonus offers, and loyalty programs. These bonus offers can give players money to play with as well as increase their chances of winning huge.
Personal privacy and also Protection
On the internet gambling enterprises additionally provide a high level of personal privacy and safety and security to gamers. Gamers can appreciate their favored video games without worrying about being seen by others or having their details stolen. Respectable online gambling establishments likewise use sophisticated encryption innovation to shield their gamers’ personal and monetary information.
Downsides of Casino Online Betting
While there are lots of benefits to gambling enterprise online gambling, there are also some disadvantages, consisting of:
Absence of Social Interaction
One more disadvantage of casino sites online gaming is the absence of social interaction. Unlike typical gambling establishments, where players can connect and also interact socially with other players as well as dealers, online casinos can feel isolating as well as lonesome. This absence of social interaction can likewise make it easier for players to create habit-forming behaviors, as they might feel extra disconnected from facts as well as much less accountable for their activities.
An additional potential downside of gambling establishment online gambling is the danger of technological concerns. Players might experience sluggish net links, software application problems, or other technical concerns that can impact their gaming experience. While respectable on the internet gambling enterprises do their finest to reduce these problems, they can still occur and also can be discouraging for gamers.
Lack of Policy
Lastly, another possible downside of gambling establishment online betting is the lack of policy. While lots of online casinos are reliable and licensed, others may operate without proper oversight or policy. This can make it challenging for gamers to recognize whether they are playing in a fair and also risk-free environment, as well as can raise the risk of fraudulence or another criminal task.
Casino Site Online Gambling: FAQs
1. Is it legal to gamble online?
– The validity of online gambling differs from nation to nation. In some locations, online betting is lawful and also managed, while in others, it might be restricted and even illegal. It is very important to inspect the legislation in your country or area before wagering online.
2. Can I play gambling establishments on the internet ready cost-free?
– Numerous internet casino sites provide free variations of their video games that can be bet fun or technique. Nonetheless, if you wish to play for actual cash, you will certainly require to make a down payment as well as wager actual cash.
3. What repayment approaches can I make use of to fund my account?
– Online online casinos typically accept a wide range of payment approaches, including debt as well as debit cards, e-wallets, financial institution transfers, and also even cryptocurrency. Make sure to examine which payment approaches are approved by your chosen online gambling enterprise.
4. How do I understand if an on-the-internet gambling establishment is risk-free and credible?
– There are several methods to examine the security and track record of an online casino. Search for licenses and also certifications from reliable betting authorities, read reviews from other players, as well as examine the online casino’s conditions to guarantee that they are fair and also clear.
5. What are the chances of winning at gambling establishment online games?
– The chances of winning at casino online games differ relying on the video game and also the details policies and also approaches involved. However, reliable internet casino sites use licensed random number generators to ensure that their games are reasonable and unbiased.
6. Can I play online casino online games on my smartphone?
– Yes, many online casino sites provide mobile versions of their games that can be accessed through tablet computers and mobile phones. Be sure to check that your chosen casino supplies a mobile-friendly system before registering.
Finally, online casino online betting is an exciting as well as preferred way to appreciate your preferred gambling enterprise games from the comfort of your very own home. Whether you’re a seasoned gambler or simply trying to find a new way to have fun, on the internet casinos supply a large range of features and also games made to match every gamer. While there are some possible drawbacks to online gaming, these can be mitigated by choosing a qualified and also trusted online gambling enterprise and setting responsible gambling limits. Why not provide it a shot as well as experience the excitement of casino online gaming for yourself?
Online casino online gaming is a kind of on-the-internet gaming that enables gamers to wager on different casino video games through the net. The background of gambling establishment online gaming can be mapped back to the mid-1990s when the very first internet casino sites were developed. Unlike typical gambling establishments, which might be limited by area or other variables, online casinos can supply hundreds or even thousands of various video games to gamers. Unlike traditional gambling enterprises, where gamers can interact socially and also connect with various other players and dealerships, online gambling establishments can feel separated and lonesome. In final thought, gambling establishment online gaming is an exciting and also preferred method to enjoy your preferred casino site video games from the comfort of your own home.

domain: game


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LifeBlood: We talked about how to trust your intuition, the danger of being too much in our heads, how to reconnect with our bodies, the benefits we get from doing it, and how to be successful in today’s world while honoring who we truly are, with Emyrald Sinclaire, intuitive guide, and spiritual mentor.
Listen to learn how to get comfortable listening to your heart and gut!
Thanks, as always for listening! If you got some value and enjoyed the show, please leave us a review here:
Stay up to date by getting our monthly updates.
Want to say “Thanks!” You can buy us a cup of coffee.

domain: psychology


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The Bradenton area and Anna Maria Island are home to award-winning bistros, cafes and restaurants. Our local restaurants have been recognized by many national magazines, including multiple times in Zagat, for their unique flavors, phenomenal locations, gulf front dining and impeccable service. From rustic beach-side Tiki Bars to elegant bistros illuminated by sunset or candlelight – meals are memories to be savored on Anna Maria Island and surrounding areas. The ambiance and views of our restaurants are as important as the foods being served. Our gulf-front or bay-side dining restaurants serve a special Anna Maria Island blend of flavor. Savor local seafood cuisine, local farm fresh dishes and local wine favored by many and admired by our worldly visitors. In addition, we boast some of the best known hamburger and barbecue eateries around. How fresh is the catch of the day? Our waters are home to grouper, red snapper, mullet and blue crab. Bay-side or gulf-side, outdoors or in, sunrise or sunset, we invite you to enjoy the secrets to island and coastal living — cool breezes, sounds of the waves crashing into the shore, star-filled skies and dining experiences like no other.
If one scoop is good then two scoops are even better! Local family business since 2007, know for its 32 flavors of homemade ice cream. We also serve a variety of casual dining choices from 9am until 10pm, at value prices.
Located on Sarasota Bay, Mar Vista is a completely unique dining experience whether you’re on the enclosed patio or under the trees. Mar Vista comes complete with its own dock, slips, private each, and package service.
Step up to a one of a kind, waterfront experience at the Beach House with good food, great friends, and a fabulous Gulf front view. Enjoy fresh, local seafood, chef-inspired features, and the area’s largest, climate controlled, outdoor deck.
We pride ourselves by creating the freshest, highest quality and most tempting cupcakes and cakes available. Choose from 18 or more delicious cupcake flavors a day or enjoy a coffee or frappe. We also offer wedding cakes & cakes for every occasion.
An artisinal, international street foods concept specializing in Argentina-style empanadas, Gluten-free Brazilian Cheese Breads and Stuffed Pasta, hand-crafted bowls, luxurious sweets, and so much more. Brunch, lunch, dinner, beer/wine, live music, take out, catering & banquet.
Experience another time when life was less complicated & when Florida could be translated into sun, fun, seafood & friends. If you haven’t experienced us yet, you’re missing a laid-back, delicious time on the waterfront in historic Cortez Village.
Eat Here is an island bistro that offers a trendy take on classic cuisine. The ambiance is casual yet sophisticated. Menu preparations are served in a variety of small sharing plates. They also feature craft beer and rare wine from around the world.
Landmark eatery established in 1998. Enjoy the freshest seafood, gourmet specialties, well stocked bar, imported beers and fine wines. Upscale casual setting with emphasis on tasteful cuisine and caring hospitality.
An award winning restaurant offering indoor & outdoor dining with views of Tampa Bay, Egmont Key & The Sunshine Skyway Bridge. Recently voted “best overall restaurant” with exceptional cuisine, fine wines & 10 lagers & ales on tap.
One of Zagat’s “Top Restaurants in America”, Beach Bistro has been the island’s most romantic, fine-dining destination for more than 30 years. Its waterfront location makes it the perfect place to catch a spectacular sunset.

domain: food