Age related differences in Endothelial response to smoke?

Buerger's disease in young men who started smoking in teen age!

In few countries Buerger's disease affecting the small blood vessels in the leg disappeared, but in the other countries it is still a problem. This disease is more often noted in the rural population or societies where childhood or teenage smoking is a problem. It gives us the suspicion that the endothelium may be responding in different ways depending on the age, but that fact was not tested and published till now. Here is one paper trying the test that hypothesis in rats.

Cigarette smoke causes oxidative stress in the lung resulting in injury and disease. The purpose of this study was to determine if there were age-related differences in cigarette smoke extract (CSE)-induced production of reactive species in single and co-cultures of alveolar epithelial type I (AT I) cells and microvascular endothelial cells harvested from the lungs (MVECLs) of neonatal, young and old male Fischer 344 rats.

Cultures of AT I cells and MVECLs grown separately (single culture) and together (co-culture) were exposed to CSE (1, 10, 50, 100%). Cultures were assayed for the production of intracellular reactive oxygen species (ROS), hydroxyl radical (OH), peroxynitrite (ONOO(-)), nitric oxide (NO) and extracellular hydrogen peroxide (H(2)O(2)). Single and co-cultures of AT I cells and MVECLs from all three ages produced minimal intracellular ROS in response to CSE. All ages of MVECLs produced H(2)O(2) in response to CSE, but young MVECLs produced significantly less H(2)O(2) compared to neonatal and old MVECLs. Interestingly, when grown as a co-culture with age-matched AT I cells, neonatal and old MVECLs demonstrated ~50% reduction in H(2)O(2) production in response to CSE. However, H(2)O(2) production in young MVECLs grown as a co-culture with young AT I cells did not change with CSE exposure. 

To begin investigating for a potential mechanism to explain the reduction in H(2)O(2) production in the co-cultures, we evaluated single and co-cultures for extracellular total antioxidant capacity. We also performed gene expression profiling specific to oxidant and anti-oxidant pathways. The total antioxidant capacity of the AT I cell supernatant was ~5 times greater than that of the MVECLs, and when grown as a co-culture and exposed to CSE (≥ 10%), the total antioxidant capacity of the supernatant was reduced by ~50%. There were no age-related differences in total antioxidant capacity of the cell supernatants. Gene expression profiling found eight genes to be significantly up-regulated or down-regulated. This is the first study to describe age-related differences in MVECLs exposed to CSE.

Microvasc Res. 2011 Nov;82(3):311-7. Epub 2011 Oct 6.

Is there an urgent need to look for medicines (Drugs) to reduce the growth of aortic aneurysms and prevent their rupture?

The incidence of abdominal aortic aneurysm increases as the advances. As the life expectancy is increasing more number of people are going to face the cardiovascular problems towards the later part of their life. In Tromso study ¹ (Norway) an aneurysm (>29 mm) was present in 8.9% men and 2.2% women (p < 0.001) aged between 25-84 years of age. Aorta > 39 mm diameter was in 2.3% of men 0.4% of women aged between 25 to 84 years. The prevalence of abdominal aortic aneurysm increased with age. In India with one billion people, we can assume that at least 10 million people will be at risk of aortic aneurysm development. It is considered that operations for aortic aneurysms are major and they are associated with high risk even in the best hospitals. The recently introduced Endorepairs (very expensive) are less invasive and considered to be associated with less pain, shorter hospital stay. But one would still ask for some medicine which can avoid intervention or operation if the aneurysms are detected early enough. So, this question of medical therapies is more relevant to us in India. On theoretical grounds, multiple medications can suppress AAA formation and subsequent expansion, reducing the risk of rupture or the need for surgical correction. However, none have been conclusively shown to reverse the pathology in the aortic wall or to have a clinically beneficial effect on slowing AAA growth. Because of potential side effects, many of these drugs remain of experimental interest only.

        However, despite the paucity of good clinical information, it would appear that there is sufficient experimental and observational evidence to support using some of these medications. It would seem appropriate to control elevations in blood pressure with ACE inhibitors or ARBs. In patients who are normotensive, either ACE inhibitors or ARBs could still be used in low doses provided patients can tolerate these medications. Addition of vitamin E should not be harmful and can be beneficial. COX-2 inhibitors in patients with concomitant arthritis or pain syndromes can have an additive benefit by reducing aneurysm expansion. Doxycycline is an inexpensive medication with few side effects. Statins should be considered in all AAA patients irrespective of cholesterol levels because of their pleiotropic effects, which might not only reduce AAA expansion but also improve overall cardiovascular risk. They can also benefit operative outcomes in patients who ultimately come to elective or emergency surgery.

Probably we can also think in terms of some kind of vaccination to prevent the progressive changes in the aortic diameter. It should become a mandatory thing in all the people above 50 years of age without smoking, above 30 year of age in case of smokers just like the vaccinations in paediatrics. The understanding at the genetic and molecular level may help us to find out a way to revert the aneurysmal changes in the aorta or its branches. It is important to invest money in this direction while continuing to think and develop mechanical solutions for the biological problems such as smooth muscle cell apoptosis, elastin degradation, inflammatory cell infiltration, synthetic abnormalities of collagen in the wall of the aorta. The proposed cost of treating the cardiovascular disease and aneurysmal disease in our country with mechanical (repetitive) means (stents and devices) is beyond imagination of the common man. So, there should be adequate encouragement, planning and funding for the development of such programs in Hospitals, Medical universities and other Educational institutions which can prevent non communicable diseases (NCDs).

[1] Reference: K Singh, KH Bonna, BK Jacobsen  et al. Prevalence of and risk factors for abdominal aortic aneurysms in a population based study. Tromso study. Am J Epidemiol 2001; 154(3): 236-44

Post lumbar puncture headache after varicose veins surgery

Headache is a complication of lumbar puncture that has been known for more than a hundred years. Post-dural puncture headache (PDPH) is characterized by the occurrence of a headache with a significant orthostatic component within 5 days of a lumbar puncture.

Patients after varicose vein surgery would like to go home on the same day or next day after surgery. But Varicose veins are generally operated under spinal anesthesia and if they develop head ache after surgery, their hospital stay gets prolonged . The incidence of head ache depends on a number of factors. Younger women with a previous history of headaches appear to be at highest risk. The incidence can be significantly reduced by using a thin lumbar puncture needle with an atraumatic tip. The condition is self-limiting and harmless, but leads to significant morbidity. Caffeine alleviates the symptoms and reduces the course of the illness. When bed rest and caffeine prove ineffective, an epidural blood patch works well for the majority, but there is no consensus on when such treatment should be offered. Headache frequently occurs after lumbar puncture for anesthesia in our hospitals. It is better to inform the patients about the same before surgery, so that their apprehensions can be relieved.  There is substantial evidence for recommending the use of a thin, atraumatic needle to reduce the incidence.

Corona Phlebectatica

Small veins ( venules ) are seen in the dermal and subdermal planes on the medial side. These fan-shaped intradermal telangiectases on the medial or lateral aspects of the foot can become troublesome in some patients. 

They can become tender, bleed or painful with small ulcerations. The significance of these veins is controversial and requires some thought. Sometimes it could be an early sign of advanced venous disease. Alternatively, it may occur in limbs with simple telangiectases elsewhere. Synonyms include malleolar flare and ankle flare.

CEAP Classification for venous disease

The field of chronic venous disorders (CVD) previously suffered from lack of precision in diagnosis. This deficiency led to conflicting reports in studies of management of specific venous problems, at a time when new methods were being offered to improve treatment for both simple and more complicated venous diseases. It was believed that these conflicts could be resolved with precise diagnosis and classification of the underlying venous problem.

TNM classification is popular for understanding the extent of cancers, their prognosis and to communicate outcomes of treatments with different people. In a similar way there has been a search for a classification to help us for better understanding chronic venous disease and communicate the results of the treatments for chronic venous disorders. The discussions of various committees on this issues resulted in CEAP classification which is also validated later on.  
The CEAP classification (Clinical-Etiology-Anatomy-Pathophysiology) was adopted worldwide to facilitate meaningful communication about CVD and serve as a basis for more scientific analysis of management alternatives. This classification, based on correct diagnosis, was also expected to serve as a systematic guide in the daily clinical investigation of patients as an orderly documentation system and basis for decisions regarding appropriate treatment.


Reference: 

• H.G. Beebe, J.J. Bergan, D. Bergqvist, B. Eklöf, I. Eriksson, M.P. Goldman et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement Vasc Surg, 30 (1996), pp. 5–11

First World Sepsis Day on Sept 13 this year.

An estimated 18 million cases of sepsis occur each year worldwide. We need to concentrate and aim to reduce the sepsis in our society and hospitals.Early goal directed therapy seems to be helpful in improving the results of treatment. 

Most important for outcome is early diagnosis, appropriate anti-infective treatment, and early goal-directed therapy that includes adequate oxygenation, correction of acidosis, fluid replacement, and use of inotropes and vasopressors.

Fighting Bacteria By Preventing Them From Talking To Each Other

Disruption of biological clocks can lead to neurodegeneration, early death, study suggests

Can we prevent the developement of antibacterial resistance?

Antibiotic resistance - Can we trace it from animal farms to the medical clinics?

The increasing incidence of hospital acquired infections with antibiotic resistant bacteria has become a major issue in the recent past. These infections due to the resistant bacteria not only increased morbidity and mortality but also increase cost of management in the hospitals. In one study from a premier medical institute in New Delhi, it was found that methicillin resistant staphylococcus bacterial infections were present in the 7.5% - 41% of cultures from these wounds from 3 different hospitals.(1).  About one quarter of healthy people carry one or more strains staphylococci asymptomatically at any given time, and infections are commonly endogenous being caused by the patient’s colonizing strain.(2). It was observed that use of antibiotics in the farm houses results in the development of resistance bacteria and it was felt this reaches the humans. Farmers regularly treat cattle, pigs, and chickens with antibiotics to dampen low-level infections that slow the growth of these animals. But wily bacteria quickly evolve resistance. Livestock farms often brim with resistant bugs that can pass to humans and potentially spread resistance to other microbes. Most farm screens have traced resistance only in pathogenic bugs—those that cause disease. But such organisms make up just a small percentage of gut microbes in pigs, The new data, he says, suggest that the common practice of using swine waste as a fertilizer is like spreading truckloads of antibiotic resistance on farmland. Those bacteria can share their resistance with other bacteria that happen to be on crops and in downstream aquatic ecosystems—bacteria that could cause illness, Chénier says. "This is a time bomb." Employees at slaughterhouses and meat-processing facilities say that they follow guidelines to keep the pigs' gut bacteria from contaminating the rest of the meat and the facility. "Risk assessment shows that by the time food gets to the consumer, there's very little resistant bacteria left in the meat".

Ecologist Martin Chénier of McGill University in Montreal, Canada, and his colleagues examined bacteria on a university farm. This farm  in January 2007 banned all antibiotics, including two commonly used varieties: tylosin and chlortetracycline. They monitored gut bacterial populations in 10 pigs by searching for bacteria resistant to common drugs in their waste.

To the team's surprise, the entire bug community kept most of its armor against the antibiotics, even after 2 ½ years. When the researchers grew the bacteria in the lab, for example, 70% to 100% of them were still resistant to chlortetracycline when the pigs were slaughtered. "I didn't expect such high levels of resistance would remain," says Chénier, whose team will publish the results in the January issue of Microbial Ecology.

References:

1) Gadepalli R et al  Clinical and molecular characteristics of nosocomial methicillin-resistant Staphylococcus aureus skin and soft tissue isolates from three Indian hospitals J Hosp Infect. 2009 Nov;73(3):253-63. Epub 2009 Sep 25.

2)  Von Eiff C, Becker K, Machka K, Stammer H, Peters G. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med. 2001; 344:11–26.

World Diabetes Day 2011

World diabetes day 14th Nov 2011

This is going to be challenge for India and Indian women to keep diabetes under control or prevent it altogether. The epidemiological surveys are saying the Indian diet, working habits, exercise patterns, better economic conditions and their genetic constitution are favoring the early onset of diabetes. So, Indian woman has to work very hard to keep herself and her family safe from the ill effects of diabetes. - Let us see the next decade and let us prove that epidemiologists are wrong once again!!! 

Endothelial progenitor cells - Vasculogenesis

Endothelial Progenitor Cells (EPCs) are immature cells. They have the capacity to proliferate, migrate and differentiate in to endothelial lineage cells.  Hematopoietic stem cells and EPCs are derived from the common precursor (hemangioblast). These two stem cells share similar surface marker antigens. They are Flk-1, Tie-2, c-Kit, Sca-1, AC133 (CD133) and CD34+.

It was interesting to note that in 1997 Asahara et al found the importance of CD34+ cells in the neovasculogenesis.  The antigens expressed on the surface differentiate the HSCs and EPCs from the leukocyte fraction of peripheral blood. CD34+ is expressed by all the HSCs but lost by the differentiated hematopoietic cells.

It was believed that the post natal neovascularisation (angiogenesis) is possible by the proliferation, migration, remodelling of the fully differentiated endothelial cells. Vasculogenesis was considered to be formation of embryonic blood vessels from the EPCs or angioblasts. Vasculogenesis begins as a cluster formation or blood island comprising angioblasts at the periphery and HSCs at the center. So, demonstration of HSCs and EPCs in the peripheral blood based on the surface antigens on them proves the fact that there are stem cells circulating in peripheral blood and they are involved in the neovasculogenesis. A potentially limiting factor in strategies designed to promote neovascularisation of ischemic tissues is the resident population of ECs, that is competent to respond to administered angiogenic cytokines.

Asahara et al felt that this issue may be successfully addressed with autologous EC transplants. The fact that progenitor ECs home to foci of angiogenesis suggests potential utility as autologous vectors for gene therapy. For antineoplastic therapies, MBCD34+ cells could be transfected with or coupled to antitumor drugs or angiogenesis inhibitors. For treatment of regional ischemia, angiogenesis could be amplified by transfection of MBCD34+ cells to achieve constitutive expression of angiogenic cytokines or provisional matrix proteins or both. In a recent study by Turan et al have shown that the circulating EPCs were reduced in patients with extensive coronary artery disease (3 vessel disease / SYNTAX score >33). We may need to understand more about this fact and bring to this point from bench to the routine bed side management of patients.

References

Asahara T, Murohara T, Sullivan  A  et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275:964-967

Turan RG, Turan Ch, Bozdag-Turam I et al. Impaired mobilization of CD 133+bone derived circulating progenitor cells with an increased number of diseased coronary arteries in ischemic heart disease patients with diabetes. Circ J 2011; 75:2635-2641