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Thứ Hai, 29 tháng 4, 2013

Diabetic Retinopathy in Southeast Asia: A Call for Ocular Telehealth Programs,





Diabetic Retinopathy in Southeast Asia: A Call for Ocular Telehealth Programs, Paolo S. Silva, et al, Vol. 27 No. 2 November 2012

Ocular Telemedicine Programs in Southeast Asia

Nearly 15 years ago, the Diabcare-Asia 1998 Study Group reported that more than half of the diabetes population in Asia is  not adequately controlled.36  Subsequently, Diabcare-Asia 2003 reported that despite  more effective and more available diabetes therapies, the patient outcomes remain disappointing and suboptimal.  Correspondingly, the prevalence of diabetic microvascular complications was higher in the patients with poor control.

One of  the  first efforts for remote diabetic retinopathy evaluation  in Southeast Asia was reported in 2000 by Ian Constable and colleagues from the Lions Eye Institute in Australia.   Widespread community-based examinations were performed using hand-held portable fundus cameras in Rural Western Australia and Surabaya, Indonesia. The resolution of the imaging devices used is low as compared to current systems but this program established the value of  digital imaging  to  extend  reach for eye care services, providing  a powerful tool for ophthalmology  health records, teaching and research  enhancing multi-specialty collaboration.  This approach to reaching into the community has  enormous potential for community screening for diabetic retinopathy and other blinding eye diseases. The ultimate goal of the program set forth by Dr. Constable remains unmet. An  inexpensive portable imaging device that is validated in terms of sensitivity and specificity of performance and is easy to use even by local health workers,  remains to  be  developed.  With the expansion of information technology and digital imaging, the  ability for  image capture, image compression,  image transmission, data storage  and  computational  analysis  of images  has advanced substantially,  potentially allowing telemedicine programs  to become more cost effective. Currently, telemedicine programs for diabetic retinopathy in Asia  are present in Indonesia, Thailand, Singapore, Malaysia and the Philippines. Although limited outcomes and sustainability data are available, given the diversity in the Southeast Asian region, these programs are potentially suited to address the emergence of diabetic retinal disease as the diabetic population grows.  


Figure 1.  Retinal images of patients with diabetes.  (A) Retina with no apparent diabetic retinopathy;  (B)  Severe traction retinal detachments; (C) Diabetic macular edema; (D) Preretinal and vitreous hemorrhage.  Images B, C and D depict the three primary causes of visual loss due to diabetic retinal disease


Comprehensive Diabetes Care and Education

Although physician and  patient knowledge of diabetic retinal complications has  increased  as a result of global informational campaigns, studies from  Indonesia, Myanmar,  Malaysia and Singapore have shown  that patient  and physician  awareness  regarding  appropriate recommendations for care and  patient awareness  of  the presence of retinopathy  are markedly inadequate.
Tajunisah and colleagues conducted a prospective survey to assess patient knowledge on the appropriate recommendations for diabetes eye care.

Over 43% of patients did not know how frequently they should follow-up with their eye care provider and over 72% did not know what  eye  treatments were available. Over 80% of patients with diabetic retinopathy identified on retinal imaging were unaware of their disease. Across Southeast Asia, approximately 50% to as high as 80% of patients do not receive the recommended eye care. Even in urban areas, eye care utilization among diabetes patients remains low and it is estimated that less than 20% of patients receive the annual recommended eye examination.

Although glycemic control and appropriate management of co-existing medical conditions  remains  the cornerstone of diabetes care,  patient education and partnership with health care providers play an increasingly important role.
Education  regarding  diabetic retinal complications may ameliorate  the unawareness of both patients and health care providers. Addressing  the emergence of diabetic retinal complications through a multidisciplinary approach that  includes  the patient and health care providers as partners in comprehensive diabetes care and education is critical in preserving vision and reducing the risk of vision loss from  diabetes. These educational strategies may be incorporated into telemedicine programs that address both patient education and decision support for health care providers. Retinal imaging provides the opportunity for  universal application of evidence-based diabetes eye care, focused, personal patient education, and coordination of diabetes care. 

Call to Action

Given the rapidly growing diabetic population in Southeast Asia, over half of which  is not achieving target glycemic  goals, it is estimated that diabetic retinal complications will  dramatically escalate  and become the leading cause of visual loss  in these regions.  Southeast Asian countries  are  traditionally viewed as ethnically diverse and  geographically dispersed.  Identification and implementation of the available strategies and initiatives that may be adopted in this setting to reduce the burden of this emerging problem  are  greatly needed.  Telemedicine efforts may provide a uniquely suited means to unite these disparate  factors and enable  the establishment of national programs for diabetic retinopathy  surveillance and treatment,  with great promise to  address this  critical emerging health issue in  this  region of  the world successfully.
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B-Scan Ultrasound is  a tool for eye disorders and diabetic retinopathy evaluation, Image from Medscape.


Ultrasound image of  asteroid hyalosis and retinal detachment on a diabetic patient.

Chủ Nhật, 28 tháng 4, 2013

Advice for Young Radiologist

James H. Thrall, MD Chairman Emeritus, Department of Radiology Massachusetts General Hospital,  Distinguished Taveras Professor of Radiology,
Harvard Medical School

What advice would you give a young radiologist entering the field today?
We posed that question to several radiology luminaries, requesting they offer words of wisdom to their newer colleagues. Digging into their experiences, they shared guidance gleaned from their careers. Find a mentor. Endeavor to improve your reports. Be a physician first. Those are just a few of the gems offered that could prove to be relevant at any stage of a radiologists career. Read on for more advice from the experts, presented here in their own words. Those entering radiology today will need to deal with continued major advances in new technology and new clinical applications of imaging. Make a commitment to career long education to learn to apply new methods and stay up-to-date. This is incredibly challenging, as I know personally from having trained before CT, MRI and PET were available clinically. Stay within your knowledge zone — you cannot do everything. Unfortunately, some, perhaps many, radiologists practice in areas outside their expertise, which is bad for patient care but also undermines the credibility of our specialty. The strength of any medical specialty over the long run depends in part on strong professional organizations. They establish technical and clinical practice standards, facilitate the exchange of new knowledge and serve as our advocates for regulatory and legislative issues. They are vital to us in the never-ending competition between specialties for turf. Make a commitment to become a member of and to actively participate in and support the radiology professional organizations related to your practice interests. For at least the last decade, dozens of radiology groups have lost their contracts each year largely because they have not correctly assessed the value equation between what they offer and how they behave versus what their hospitals are looking for. The days of protective manpower shortages and entitled behavior are over. More than ever, radiologists now need to be active participants in their institutions beyond interpreting imaging studies and be regarded as good citizens in their institutions. Hospitals are looking for team-oriented physicians who understand organizational needs in care coordination, quality and safety and operational efficiency among other topics. Make a career long commitment to participating within your institution on committees, in medical staff governance, community outreach and in other supporting activities. Become a leader and someone who is regarded as exemplifying the best in organizational values and behavior.

Thứ Bảy, 27 tháng 4, 2013

Sinh nhật lần thứ 60 của DNA, Nguyễn văn Tuấn

http://25.media.tumblr.com/tumblr_meedyajgxE1qza6bio1_500.jpgÍt người để ý rằng hôm nay là một ngày đáng ghi nhớ: đó là ngày “ra đời” của DNA. Sáu chục năm trước, đúng vào ngày này (25/4/1953), tập san Nature của Anh công bố 3 bài báo mô tả cấu trúc của DNA. Từ đó đến nay, di truyền học đã bước sang một giai đoạn mới, và dĩ nhiên là không ngừng tiến bộ, nhưng những tiến bộ mới vẫn chỉ xây dựng trên cấu trúc của DNA. Nhưng khi nói đến khám phá DNA, công chúng thường chỉ nghe đến hai cái tên Watson và Crick (hay có khi thêm Wilkins), mà ít ai nghe đến 4 nhân vật khác cũng có đóng góp rất quan trọng cho khám phá mang tính lịch sử này.  

Ngày 25/4/1953 Tập san Nature của Anh công bố 3 bài báo mô tả một khám phá di truyền rất quan trọng: cấu trúc của DNA. Một bài báo của James Watson và Francis Crick (lúc đó thuộc ĐH Cambridge) đề xướng cái mà chúng ta ngày nay biết đến là double helix – xoán kép [1]. Hai bài báo song song khác là của Maurice Wilkins [2] và Rosalind Franklin [3] (thuộc King’s College, London), mô tả phương pháp X quang dùng để yểm trợ cho giả thuyết double helix. Sự đột phá này đã mở ra một kỉ nguyên mới cho sinh học phân tử và y học hiện đại. Có thể nói không ngoa rằng hầu hết những phát triển về di truyền học trong thời gian 50 năm qua dựa vào nền tảng của DNA. 
Bài báo của Watson và Crick không có dữ liệu thí nghiệm nào cả; tất cả chỉ là suy luận. Nhưng là suy luận thuộc đẳng cấp Nobel. Trong khi đó, hai bài của Wilkins và Franklin có dữ liệu yểm trợ. Nhưng Watson và Crick không đề cập đến những công trình nghiên cứu của Wilkins và Franklin!
Nói đến khám phá DNA, người ta chỉ nghĩ (hay nghe) đến hai cái tên quen thuộc: Watson – Crick. Nhưng ít ai nghe đến những nhân vật cũng có đóng góp rất quan trọng cho việc khám phá cấu trúc DNA là Rosalind Franklin và Maurice Wilkins. Càng ít người biết đến John Randall và Raymond Gosling, những người có thể nói là đi tiên phong trong công trình nghiên cứu về DNA thời đó. Nhưng giải Nobel y sinh học năm 1962 được trao cho 3 người: Watson, Crick, và Wilkins.
Rosalind Franklin sinh năm 1920 trong một gia đình gốc Do Thái, là một nhà sinh vật lí học (biophysicist), một chuyên gia về tinh thể học (crystallography). Năm 1951, bà được Giáo sư John Randall tuyển dụng về làm việc tại trường King’s College trong nhóm nghiên cứu sinh vật lí học. Bà nổi tiếng là một người giỏi về thiết kế thí nghiệm và rất nghiêm chỉnh trong khoa học. Là nữ mà làm trong một nhóm nghiên cứu nổi tiếng là một điều “lạ” thời đó, nhưng bà đã vượt qua tất cả những xầm xì và mỉa mai bằng trí thông minh và kĩ năng tuyệt vời của mình. Bà được Giáo sư John Randall giao nhiệm vụ dùng X quang để nghiên cứu cấu trúc protein, nhưng sau này vì lí do nào đó, ông lại giao bà công việc nghiên cứu cấu trúc DNA và bà đã thành công. Sự thành công của bà một phần là nhờ vào đột phá của người học trò là Raymond Gosling. Người ta cho rằng bà Franklin xứng đáng được trao giải Nobel, nhưng việc đó không xảy ra vì bà qua đời năm 1958, tức 4 năm trước khi giải Nobel được trao cho Watson, Crick, và Wilkins.
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Raymond Gosling là hai (người kia là James Watson) còn sống trong số 7 tác giả của 3 bài báo trên Nature. Gosling (sinh năm 1926) là một nhà vật lí, nhưng nghiên cứu về sinh học. Ông là học trò của Maurice Wilkins và Roselind Franklin tại King’s College, và tốt nghiệp tiến sĩ năm 1954. Theo lời kể của Giáo sư Raymond Gosling (xem tập san Genome Biology số ra tuần này) thì chính ông, dưới sự hướng dẫn của John Randall, mới là người đầu tiên kết tinh gene. Chính sự đột phá đó đã dẫn đến khám phá DNA. Ông muốn người đời sau ghi công người hướng dẫn ông là Giáo sư John Randall (sau này trở thành “Sir”).
http://upload.wikimedia.org/wikipedia/commons/f/f6/Raymond_Gosling.jpg
Gs Raymond Gosling, học trò của Rosalind Franklin và Maurice Wilkins

John Randall (1905-1984) cũng là một nhà vật lí, nhưng được Giáo sư Gosling xem là “người đi trước thời đại”. Chính ông là người sáng lập ra nhóm nghiên cứu Biophysics được sự tài trợ của Medical Research Council (Hội đồng Nghiên cứu Y khoa – MRC). Ông là người định hướng ứng dụng vật lí trong nghiên cứu sinh học và giải cho được cấu trúc của DNA. Ông tuyển dụng Rosalind Franklin, và giao cho bà nhiệm vụ để thực hiện định hướng này cùng với phó trưởng nhóm của ông là Maurice Wilkins. Nhưng bà Franklin và ông Wilkins không thuận nhau, nên hai người làm một hướng. (Sau này thì Wilkins được giải Nobel năm 1962). Theo Giáo sư Raymond Gosling, Giáo sư John Randall mới chính là người cần được vinh danh trong khám phá cấu trúc DNA. Dù Randall không không trực tiếp làm, nhưng tầm nhìn của ông đã dẫn đến một định hướng làm thay đổi khoa học trong thế kỉ 20 và sau này.
http://www.packer34.freeserve.co.uk/sirjohnrandallSKETCH.jpg
John Randall
Tuần vừa qua, Time có đăng một bài ca ngợi và vinh danh bà Rosalind Franklin nhân dịp kỉ niệm 60 năm ngày cấu trúc DNA được khám phá. Sau khi đọc bài này, Gs Raymond Gosling viết một lá thư nhắc nhở Time rằng một người có thể quan trọng hơn cần được ghi nhận chính là Gs John Randall.
Một nhân vật thầm lặng khác trong khám phá cấu trúc DNA là Alex Stokes. Gs Stokes là đồng tác giả bài báo trên Nature 1953 (cùng với Maurice Wilkins và Herbert Wilson) [2]. Công trạng của Alex Stokes là ông đã đề xuất một mô hình toán học để diễn giải nhiễu xạ X quang. Nếu không có mô hình của Stokes, Gs Gosling cho biết, nhóm nghiên cứu sẽ không thể nào hiểu được ý nghĩa của dữ liệu.
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Alex Stokes
Một người khác trong nhóm 7 người liên quan đến công trình DNA làHerbert Wilson (1929-2008). Wilson cũng là một nhà vật lí, và làm việc dưới quyền của Gs John Randall. Sau này, Gs Wilson trở thành Fellow of Royal Society (giống như viện sĩ viện hàn lâm) của Anh.
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Herbert Wilson
Đằng sau mỗi công trình khoa học mang tính lịch sử đều có những câu chuyện thú vị về những cá nhân liên quan. Trong thời gian qua, phần lớn công chúng chỉ nghe đến ba người Watson, Crick, và [ít hơn] Wilkins khi đề cập đến khám phá DNA. Nhưng thật ra, đằng sau công trình đó có đến 7 người. Bốn người ít được nhắc đến nhưng có đóng góp quan trọng là Rosalind Franklin, Raymond Gosling, Alex Stokes, và Herbert Wilson. Mỗi người một cá tính, có khi họ có mâu thuẫn cá nhân với nhau, dù tất cả đều làm việc vì mục tiêu chung. Nhưng nếu những gì Gs Raymond Gosling nói là đúng (và chúng ta không có lí do gì để nghi ngờ ông) thì người đi trước 7 nhân vật kia chính là Gs John Randall.

Tham khảo và chú thích:
1. Watson JD, Crick FH: Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.Nature 1953, 171:737-738.
2. Wilkins MHF, Stokes AR, Wilson HR: Molecular structure of deoxypentose nucleic acids.Nature 1953, 171:738-740.
3. Franklin RE, Gosling RG: Molecular configuration in sodium thymonucleate.Nature 1953, 171:740-741.

****
Sau đây là bài báo lịch sử 1 trang của Watson và Crick, kèm theo chú giải của một chuyên gia. Bài báo này còn được xem là một mẫu mực trong văn phong khoa học: ngắn, gọn, đi thẳng vào vấn đề. Những chỗ đánh dấu (1), (2), v.v. là chú giải phía dưới bài báo.Nguồn: http://www.exploratorium.edu/origins/coldspring/printit.html

A Structure for Deoxyribose Nucleic Acid

J. D. Watson and F. H. C. Crick (1)
April 25, 1953 (2), Nature (3), 171, 737-738
We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest. 
A structure for nucleic acid has already been proposed by Pauling (4) and Corey1. They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons:
(1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other.
(2) Some of the van der Waals distances appear to be too small.
Another three-chain structure has also been suggested by Fraser (in the press). In his model the phosphates are on the outside and the bases on the inside, linked together by hydrogen bonds. This structure as described is rather ill-defined, and for this reason we shall not comment on it.

We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid (5). This structure has two helical chains each coiled round the same axis (see diagram). We have made the usual chemical assumptions, namely, that each chain consists of phosphate diester groups joining beta-D-deoxyribofuranose residues with 3',5' linkages. The two chains (but not their bases) are related by a dyad perpendicular to the fibre axis. Both chains follow right-handed helices, but owing to the dyad the sequences of the atoms in the two chains run in opposite directions (6) . Each chain loosely resembles Furberg's2model No. 1 (7); that is, the bases are on the inside of the helix and the phosphates on the outside. The configuration of the sugar and the atoms near it is close to Furberg's "standard configuration," the sugar being roughly perpendicular to the attached base. There is a residue on each every 3.4 A. in the z-direction. We have assumed an angle of 36° between adjacent residues in the same chain, so that the structure repeats after 10 residues on each chain, that is, after 34 A. The distance of a phosphorus atom from the fibre axis is 10 A. As the phosphates are on the outside, cations have easy access to them.
Figure 1
This figure is purely diagrammatic (8). The two ribbons symbolize the two phophate-sugar chains, and the horizonal rods the pairs of bases holding the chains together. The vertical line marks the fibre axis.
The structure is an open one, and its water content is rather high. At lower water contents we would expect the bases to tilt so that the structure could become more compact.

The novel feature of the structure is the manner in which the two chains are held together by the purine and pyrimidine bases. The planes of the bases are perpendicular to the fibre axis. They are joined together in pairs, a single base from one chain being hydroden-bonded to a single base from the other chain, so that the two lie side by side with identical z-coordinates. One of the pair must be a purine and the other a pyrimidine for bonding to occur. The hydrogen bonds are made as follows: purine position 1 to pyrimidine position 1; purine position 6 to pyrimidine position 6.
If it is assumed that the bases only occur in the structure in the most plausible tautomeric forms (that is, with the keto rather than the enol configurations) it is found that only specific pairs of bases can bond together. These pairs are: adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine) (9).
In other words, if an adenine forms one member of a pair, on either chain, then on these assumptions the other member must be thymine; similarly for guanine and cytosine. The sequence of bases on a single chain does not appear to be restricted in any way. However, if only specific pairs of bases can be formed, it follows that if the sequence of bases on one chain is given, then the sequence on the other chain is automatically determined.

It has been found experimentally3,4 that the ratio of the amounts of adenine to thymine, and the ratio of guanine to cytosine, are always very close to unity for deoxyribose nucleic acid.

It is probably impossible to build this structure with a ribose sugar in place of the deoxyribose, as the extra oxygen atom would make too close a van der Waals contact.

The previously published X-ray data5,6 on deoxyribose nucleic acid are insufficient for a rigorous test of our structure. So far as we can tell, it is roughly compatible with the experimental data, but it must be regarded as unproved until it has been checked against more exact results. Some of these are given in the following communications (10). We were not aware of the details of the results presented there when we devised our structure (11), which rests mainly though not entirely on published experimental data and stereochemical arguments.

It has not escaped our notice (12) that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.Full details of the structure, including the conditions assumed in building it, together with a set of coordinates for the atoms, will be published elsewhere (13).We are much indebted to Dr. Jerry Donohue for constant advice and criticism, especially on interatomic distances. We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King’s College, London. One of us (J. D. W.) has been aided by a fellowship from the National Foundation for Infantile Paralysis.

1 Pauling, L., and Corey, R. B., Nature, 171, 346 (1953); Proc. U.S. Nat. Acad. Sci., 39, 84 (1953).
2 Furberg, S., Acta Chem. Scand., 6, 634 (1952).
3 Chargaff, E., for references see Zamenhof, S., Brawerman, G., and Chargaff, E., Biochim. et Biophys. Acta, 9, 402 (1952).
4 Wyatt, G. R., J. Gen. Physiol., 36, 201 (1952).
5 Astbury, W. T., Symp. Soc. Exp. Biol. 1, Nucleic Acid, 66 (Camb. Univ. Press, 1947).
6 Wilkins, M. H. F., and Randall, J. T., Biochim. et Biophys. Acta, 10, 192 (1953).

Annotations

(1) It’s no surprise that James D. Watson and Francis H. C. Crick spoke of finding the structure of DNA within minutes of their first meeting at the Cavendish Laboratory in Cambridge, England, in 1951. Watson, a 23-year-old geneticist, and Crick, a 35-year-old former physicist studying protein structure for his doctorate in biophysics, both saw DNA’s architecture as the biggest question in biology. Knowing the structure of this molecule would be the key to understanding how genetic information is copied. In turn, this would lead to finding cures for human diseases.
Aware of these profound implications, Watson and Crick were obsessed with the problem—and, perhaps more than any other scientists, they were determined to find the answer first. Their competitive spirit drove them to work quickly, and it undoubtedly helped them succeed in their quest.
Watson and Crick’s rapport led them to speedy insights as well. They incessantly discussed the problem, bouncing ideas off one another. This was especially helpful because each one was inspired by different evidence. When the visually sensitive Watson, for example, saw a cross-shaped pattern of spots in an X-ray photograph of DNA, he knew DNA had to be a double helix. From data on the symmetry of DNA crystals, Crick, an expert in crystal structure, saw that DNA’s two chains run in opposite directions.
Since the groundbreaking double helix discovery in 1953, Watson has used the same fast, competitive approach to propel a revolution in molecular biology. As a professor at Harvard in the 1950s and 1960s, and as past director and current president of Cold Spring Harbor Laboratory, he tirelessly built intellectual arenas—groups of scientists and laboratories—to apply the knowledge gained from the double helix discovery to protein synthesis, the genetic code, and other fields of biological research. By relentlessly pushing these fields forward, he also advanced the view among biologists that solving major health problems requires research at the most fundamental level of life.
(2) On this date, Nature published the paper you are reading.
According to science historian Victor McElheny of the Massachusetts Institute of Technology, this date was a turning point in a longstanding struggle between two camps of biology, vitalism and reductionism. While vitalists studied whole organisms and viewed genetics as too complex to understand fully, reductionists saw deciphering fundamental life processes as entirely possible—and critical to curing human diseases. The discovery of DNA’s double-helix structure was a major blow to the vitalist approach and gave momentum to the reductionist field of molecular biology.
Historians wonder how the timing of the DNA race affected its outcome. Science, after years of being diverted to the war effort, was able to focus more on problems such as those affecting human health. Yet, in the United States, it was threatened by a curb on the free exchange of ideas. Some think that American researcher Linus Pauling would have beaten Watson and Crick to the punch if Pauling’s ability to travel had not been hampered in 1952 by the overzealous House Un-American Activities Committee.
(3) Nature (founded in 1869)——and hundreds of other scientific journals—help push science forward by providing a venue for researchers to publish and debate findings. Today, journals also validate the quality of this research through a rigorous evaluation called peer review. Generally at least two scientists, selected by the journal’s editors, judge the quality and originality of each paper, recommending whether or not it should be published.
Science publishing was a different game when Watson and Crick submitted this paper to Nature. With no formal review process at most journals, editors usually reached their own decisions on submissions, seeking advice informally only when they were unfamiliar with a subject.
(4) The effort to discover the structure of DNA was a race among several players. They were world-renowned chemist Linus Pauling at the California Institute of Technology, and X-ray crystallographers Maurice Wilkins and Rosalind Franklin at King’s College London, in addition to Watson and Crick at the Cavendish Laboratory, Cambridge University.
The competitive juices were flowing well before the DNA sprint was in full gear. In 1951, Pauling narrowly beat scientists at the Cavendish Lab, a top center for probing protein structure, to the discovery that certain proteins are helical. The defeat stung. When Pauling sent a paper to be published in early 1953 that proposed a three-stranded DNA structure, the head of the Cavendish gave Watson and Crick permission to work full-time on DNA’s structure. Cavendish was not about to lose twice to Pauling.
Pauling's proposed structure of DNA was a three-stranded helix with the bases facing out. While the model was wrong, Watson and Crick were sure Pauling would soon learn his error, and they estimated that he was six weeks away from the right answer. Electrified by the urgency—and by the prospect of beating a science superstar—Watson and Crick discovered the double helix after a four-week frenzy of model building.
Pauling was foiled in his attempts to see X-ray photos of DNA from King's College—crucial evidence that inspired Watson's vision of the double helix—and had to settle for inferior older photographs. In 1952, Wilkins and the head of the King's laboratory had denied Pauling's request to view their photos. Pauling was planning to attend a science meeting in London, where he most likely would have renewed his request in person, but the United States House Un-American Activities Committee halted Pauling’s trip, citing his antiwar activism. It was fitting, then, that Pauling, who won the Nobel Prize in Chemistry in 1954, also won the Nobel Peace Prize in 1962, the same year Watson and Crick won their Nobel Prize for discovering the double helix.
(5) Here, the young scientists Watson and Crick call their model “radically different” to strongly set it apart from the model proposed by science powerhouse Linus Pauling. This claim was justified. While Pauling’s model was a triple helix with the bases sticking out, the Watson-Crick model was a double helix with the bases pointing in and forming pairs of adenine (A) with thymine (T), and cytosine (C) with guanine (G).
(6) This central description of the double helix model still stands today—a monumental feat considering that the vast majority of research findings are either rejected or changed over time.
According to science historian Victor McElheny of the Massachusetts Institute of Technology, the staying power of the double helix theory puts it in a class with Newton’s laws of motion. Just as Newtonian physics has survived centuries of scientific scrutiny to become the foundation for today’s space programs, the double helix model has provided the bedrock for several research fields since 1953, including the biochemistry of DNA replication, the cracking of the genetic code, genetic engineering, and the sequencing of the human genome.
(7) Norwegian scientist Sven Furberg’s DNA model—which correctly put the bases on the inside of a helix—was one of many ideas about DNA that helped Watson and Crick to infer the molecule’s structure. To some extent, they were synthesizers of these ideas. Doing little laboratory work, they gathered clues and advice from other experts to find the answer. Watson and Crick’s extraordinary scientific preparation, passion, and collaboration made them uniquely capable of this synthesis.
(8) A visual representation of Watson and Crick’s model was crucial to show how the components of DNA fit together in a double helix. In 1953, Crick’s wife, Odile, drew the diagram used to represent DNA in this paper. Scientists use many different kinds of visual representations of DNA.
(9) The last hurdle for Watson and Crick was to figure out how DNA’s four bases paired without distorting the helix. To visualize the answer, Watson built cardboard cutouts of the bases. Early one morning, as Watson moved the cutouts around on a tabletop, he found that only one combination of base molecules made a DNA structure without bulges or strains. As Crick put it in his book What Mad Pursuit, Watson solved the puzzle “not by logic but serendipity.” Watson and Crick picked up this model-building approach from eminent chemist Linus Pauling, who had successfully used it to discover that some proteins have a helical structure.
(10) Alongside the Watson-Crick paper in the April 25, 1953, issue of Nature were separately published papers by scientists Maurice Wilkins and Rosalind Franklin of King’s College, who worked independently of each other. The Wilkins and Franklin papers described the X-ray crystallography evidence that helped Watson and Crick devise their structure. The authors of the three papers, their lab chiefs, and the editors of Nature agreed that all three would be published in the same issue.
The “following communications” that our authors are referring to are the papers by Franklin and Wilkins, published on the journal pages immediately after Watson and Crick’s paper. They (and other papers) can be downloaded as PDF files (Adobe Acrobat required) from Nature’s 50 Years of DNA website (http://www.nature.com/nature/dna50/archive.html).
Here are the direct links:
Molecular Configuration in Sodium Thymonucleate
Franklin, R., and Gosling, R. G.
Nature 171, 740-741 (1953)
URL: http://www.nature.com/nature/dna50/franklingosling.pdf
Molecular Structure of Deoxypentose Nucleic Acids
Wilkins, M. H. F., Stokes, A. R., & Wilson, H. R.
Nature 171, 738-740 (1953)
URL: http://www.nature.com/nature/dna50/wilkins.pdf
(11) This sentence marks what many consider to be an inexcusable failure to give proper credit to Rosalind Franklin, a King’s College scientist. Watson and Crick are saying here that they “were not aware of” Franklin’s unpublished data, yet Watson later admits in his book The Double Helix that these data were critical in solving the problem. Watson and Crick knew these data would be published in the same April 25 issue of Nature, but they did not formally acknowledge her in their paper.
What exactly were these data, and how did Watson and Crick gain access to them? While they were busy building their models, Franklin was at work on the DNA puzzle using X-ray crystallography, which involved taking X-ray photographs of DNA samples to infer their structure. By late February 1953, her analysis of these photos brought her close to the correct DNA model.
But Franklin was frustrated with an inhospitable environment at King’s, one that pitted her against her colleagues. And in an institution that barred women from the dining room and other social venues, she was denied access to the informal discourse that is essential to any scientist’s work. Seeing no chance for a tolerable professional life at King’s, Franklin decided to take another job. As she was preparing to leave, she turned her X-ray photographs over to her colleague Maurice Wilkins (a longtime friend of Crick).
Then, in perhaps the most pivotal moment in the search for DNA’s structure, Wilkins showed Watson one of Franklin’s photographs without Franklin’s permission. As Watson recalled, “The instant I saw the picture my mouth fell open and my pulse began to race.” To Watson, the cross-shaped pattern of spots in the photo meant that DNA had to be a double helix.
Was it unethical for Wilkins to reveal the photographs? Should Watson and Crick have recognized Franklin for her contribution to this paper? Why didn’t they? Would Watson and Crick have been able to make their discovery without Franklin’s data? For decades, scientists and historians have wrestled over these issues.
To read more about Rosalind Franklin and her history with Wilkins, Watson, and Crick, see the following:
“Light on a Dark Lady” by Anne Piper, a lifelong friend of Franklin’s
URL: http://www.physics.ucla.edu/~cwp/articles/franklin/piper.html
“The Double Helix and the Wronged Heroine,” an essay on Nature’s “Double Helix: 50 years of DNA” Web site
URL: http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v421/n6921/full/nature01399_fs.html
A review of Brenda Maddox’s recent book, Rosalind Franklin: The Dark Lady of DNA in The Guardian (UK)
URL:http://books.guardian.co.uk/whitbread2002/story/0,12605,842764,00.html
(12) This phrase and the sentence it begins may be one of the biggest understatements in biology. Watson and Crick realized at the time that their work had important scientific implications beyond a “pretty structure.” In this statement, the authors are saying that the base pairing in DNA (adenine links to thymine and guanine to cytosine) provides the mechanism by which genetic information carried in the double helix can be precisely copied. Knowledge of this copying mechanism started a scientific revolution that would lead to, among other advances in molecular biology, the ability to manipulate DNA for genetic engineering and medical research, and to decode the human genome, along with those of the mouse, yeast, fruit fly, and other research organisms.
(13) This paper is short because it was intended only to announce Watson and Crick’s discovery, and because they were in a competitive situation. In January 1954, they published the “full details” of their work in a longer paper (in Proceedings of the Royal Society). This “expound later” approach was usual in science in the 1950s as it continues to be. In fact, Rosalind Franklin did the same thing, supplementing her short April 25 paper with two longer articles.
Today, scientists publish their results in a variety of formats. They also present their work at conferences. Watson reported his and Crick’s results at the prestigious annual symposium at Cold Spring Harbor Laboratory in June 1953. As part of our recognition of the fiftieth anniversary of the double helix discovery, we will join scientists at Cold Spring Harbor as they present their papers at the “Biology of DNA” conference.

Thứ Sáu, 26 tháng 4, 2013

Ultrasound is Effective for Differentiation of Perforated from Nonperforated Appendicitis in Children.


ABSTRACT :

OBJECTIVE. Acute appendicitis is the most common condition requiring emergency surgery in children. Differentiation of perforated from nonperforated appendicitis is important because perforated appendicitis may initially be managed conservatively whereas nonperforated appendicitis requires immediate surgical intervention. CT has been proved effective in identifying appendiceal perforation. The purpose of this study was to determine whether perforated and nonperforated appendicitis in children can be similarly differentiated with ultrasound.

MATERIALS AND METHODS. This retrospective study included 161 consecutively registered children from two centers who had acute appendicitis and had undergone ultra-sound and appendectomy. Ultrasound images were reviewed for appendiceal size, appearance of the appendiceal wall, changes in periappendiceal fat, and presence of free fluid, abscess, or appendicolith. The surgical report served as the reference standard for determining whether perforation was present. The specificity and sensitivity of each ultrasound finding were determined, and binary models were generated.

RESULTS. The patients included were 94 boys and 67 girls (age range, 1–20 years; mean, 11 ± 4.4 [SD] years) The appendiceal perforation rate was significantly higher in children younger than 8 years (62.5%) compared with older children (29.5%). Sonographic findings associated with perforation included abscess (sensitivity, 36.2%; specificity, 99%), loss of the echogenic submucosal layer of the appendix in a child younger than 8 years (sensitivity, 100%; specificity, 72.7%), and presence of an appendicolith in a child younger than 8 years (sensitivity, 68.4%; specificity, 91.7%).

CONCLUSION. Ultrasound is effective for differentiation of perforated from nonperforated appendicitis in children.


 

Enterovesical Fistula: Sonographic Diagnosis


A 73-year-old man presented to the emergency department after noting dysuria and fecal matter in his urine for 1 day. The patient had a medical history consisting of prostate cancer treated with brachytherapy, Crohn disease, colonic stricture, diabetes, and no prior surgeries. Other than episodic lower abdominal pain that had been occurring for months, the patient did not have any additional symptoms, denying any fever, chills, vomiting, diarrhea, constipation, rectal pain, chest pain, or dyspnea.
On initial examination, the patient was in no acute distress, afebrile, and hemodynamically stable. His abdomen was soft with mild tenderness of the lower abdomen without palpable masses, guarding, rigidity, or rebound. There was no scrotal or inguinal swelling or tenderness. Initial laboratory results were notable only for a white blood cell count of 14,100 cells/μL with 88% neutrophils and a venous lactate level of 0.83 mmol/L. Fecal matter was noted on gross examination of the urine, and urinalysis results were negative for nitrite, positive for leukocyte esterase, and showed more than 182 white blood cells per high-power field and many bacteria.
Point-of-care sonography was performed by the emergency physician using a curvilinear transducer (Figure 1, A and B, and Video 1) and revealed a collection of mixed echogenicity throughout the bladder, representing stool, along with multiple hyperechoic foci with a reverberation artifact and shadowing, consistent with pneumaturia. A hyperechoic band leading from the bowel into the bladder was noted, consistent with a fistula. A computed tomographic (CT) scan of the abdomen and pelvis (Figure 1C) was obtained to assess for associated intra-abdominal disease and to provide further anatomic detail given the patient’s complicated history. Computed tomography revealed a heterogeneous collection of soft tissue and fecal matter within the pelvis bordering the posterosuperior wall of the bladder and air within the bladder, supporting the diagnosis of an enterovesical fistula. Subsequent surgical exploration and cystoscopy confirmed a colovesical fistula from the distal sigmoid to the left bladder near the left ureteral orifice and copious stool within the bladder.
Enterovesical fistulas are classified as colovesical, which is the most common form, rectovesical, ileovesical, and appendicovesical. Most commonly a complication of diverticulitis, malignancy, or Crohn disease,1 fistulas may also occur after trauma, pelvic surgery, or pelvic radiation therapy, including brachytherapy.2 The fistula is often difficult to identify on imaging studies; hence the lack of a reference standard imaging modality.3 The most sensitive and commonly recommended initial study is CT,1,3 although the fistula itself is not consistently identified.37 Findings used to confirm the presence of a fistula include gas in the bladder in patients without recent urinary instrumentation, local colonic thickening immediately adjacent to an area of locally thickened bladder, and oral contrast medium in the bladder on nonintravenous contrast-enhanced CT.1,4,8 Alternatively, intravenous contrast medium noted within the bowel when an oral contrast medium is not used also implies the presence of a fistula.6
Like CT, sonography can visualize soft tissue in multiple planes and has been used in the diagnosis of colovesical fistulas.911 Suggestive findings include pneumaturia, which is represented by multiple reverberation artifacts within the bladder, and stool within the bladder, which is hyperechoic.9,10 The fistula itself appears hypoechoic,12 but if gas is present in the tract, the fistula may instead be visualized as a hyperechoic “beak” connecting the peristaltic bowel lumen and the bladder. Air bubbles or hyperechoic material may be noted flowing from the beak into the bladder with direct compression either manually or using the ultrasound transducer.9,11 This finding must be distinguished from ureteral jets emanating from the ureterovesical junction due to normal peristalsis of the ureter.9,11



Figure 1.
Enterovesical fistula in a 73-year-old man. A and B, Longitudinal (A) and transverse (B) views of the suprapubic window illustrating the bladder (B) with a hyperechoic artifact consistent with air (A) and heterogeneous material consistent with stool (S). There is a hyperechoic band connecting the bowel to the inside of the bladder, consistent with a fistula (F). C, Transverse CT scan of the pelvis illustrating air within the bladder.
In contrast to CT, sonography is used infrequently in the initial evaluation of suspected enterovesical fistulas. In addition to identifying the presence of a fistula, CT may reveal associated intra-abdominal processes and provides anatomic details for any surgical planning. There are also limited data regarding the sensitivity of sonography for diagnosing these fistulas. Sonography did not identify any fistulas in 27 patients from 3 retrospective studies with confirmed enterovesical fistulas.3,4,13 In another retrospective study of patients with colovesical fistulas secondary to diverticulitis, sonography identified a fistula in 1 of 23 patients.14 None of these studies, though, describe the experience of the sonographers or specific imaging protocols. In a prospective study by Maconi et al,15 sonography enabled the diagnosis of all 4 enterovesical fistulas in patients with Crohn disease who underwent surgical intervention.
The diagnosis of an enterovesical fistula is strongly suggested by the presence of fecaluria, pneumaturia, or recurrent urinary tract infections, but it may present more subtly. Fewer than half of affected patients have fecaluria, and although pneumaturia is found in approximately 60% of patients, other causes such as recent bladder instrumentation and emphysematous cystitis must be considered.1 Although this patient presented with classic signs of an enterovesical fistula, this case shows that point-of-care sonography can be used to make the diagnosis. As it is performed at the bedside, it may be used early in the course of evaluation, especially when the patient’s presentation is less clear and CT not immediately indicated. Findings suggestive of a fistula, including air or stool in the bladder, or visualization of the fistula itself, can lead to timely diagnosis of this disease process. Furthermore, especially if pain, fever, and unstable vital signs are present, point-of-care sonography allows for concomitant evaluation for other possible causes of these symptoms and guiding of further interventions.

Tablet Ultrasound

Tablet Ultrasound System Provides Easy Access to Point-of-Care Imaging
By Medimaging International staff writersPosted on 23 Apr 2013

Image: The MobiUSTC1 tablet ultrasound system (Photo courtesy of Mobisante).
Image: The MobiUSTC1 tablet ultrasound system (Photo courtesy of Mobisante).
A newly developed tablet ultrasound system provides high-resolution, point-of-care (POC) ultrasound imaging within reach of healthcare professionals everywhere, helping them practice better medicine and reduce costs. The system supports a quick look, triage, routine screening, and ultrasound-guided procedures.

Mobisante (Redmond, WA, USA) reported on the release of the MobiUSTC1 tablet ultrasound system, which is built upon the success and novel features of the MobiUS SP1 smartphone ultrasound system. The MobiUS TC1 ultrasound system is a suitable choice for clinics, emergency departments, rural and community hospitals, disaster relief organizations, and the uniformed services.

Exploiting the strength and ubiquity of sophisticated mobile computing technology, the MobiUS systems are available at a fraction of the cost of typical ultrasound systems. They utilize standards-based technology for easy implementation and shorter learning curves. The MobiUS TC1 is very mobile and compact to fit into a wide range of settings, and provides instant connectivity through Wi-Fi.

Sailesh Chutani, CEO and cofounder of Mobisante, stated, “Devices like MobiUS TC1 enable more care to be provided outside of expensive settings like hospitals into settings that are less expensive, such as clinics and other locations where the patient needs immediate care. This is key to improving access while reducing costs.”

The system enables diagnosis and treatment in trauma (FAST [focused assessment with sonography for trauma] exam, lung, cardiac screening), abdominal pain, abdominal aortic aneurysm (AAA) and other routine screening such as bladder assessment, ob/gyn evaluations, triage, and ultrasound-guided procedures. The tablet also supports endocavity probes for gynecology or prostate imaging, in addition to the already wide array of probes that cover multiple clinical applications.

Mobisante, Inc. is focused on providing safe, simple, noninvasive, and cost-effective ultrasound technology available to a wide range of clinicians. By utilizing the steadily increasing power and ubiquity of, standards-based mobile computing technology, the company is able to provide simpler, flexible, and lower cost solutions that contrast to the costly and complex products that previously restricted broad access to point of care medical imaging.

Related Links:

Mobisante

 

Fine Particulate Air Pollution and the Progression of Carotid Intima-Medial Thickness




Background

Fine particulate matter (PM2.5) has been linked to cardiovascular disease, possibly via accelerated atherosclerosis. We examined associations between the progression of the intima-medial thickness (IMT) of the common carotid artery, as an indicator of atherosclerosis, and long-term PM2.5 concentrations in participants from the Multi-Ethnic Study of Atherosclerosis (MESA).

Methods and Results

MESA, a prospective cohort study, enrolled 6,814 participants at the baseline exam (2000–2002), with 5,660 (83%) of those participants completing two ultrasound examinations between 2000 and 2005 (mean follow-up: 2.5 years). PM2.5 was estimated over the year preceding baseline and between ultrasounds using a spatio-temporal model. Cross-sectional and longitudinal associations were examined using mixed models adjusted for confounders including age, sex, race/ethnicity, smoking, and socio-economic indicators. Among 5,362 participants (5% of participants had missing data) with a mean annual progression of 14 µm/y, 2.5 µg/m3 higher levels of residential PM2.5 during the follow-up period were associated with 5.0 µm/y (95% CI 2.6 to 7.4 µm/y) greater IMT progressions among persons in the same metropolitan area. Although significant associations were not found with IMT progression without adjustment for metropolitan area (0.4 µm/y [95% CI −0.4 to 1.2 µm/y] per 2.5 µg/m3), all of the six areas showed positive associations. Greater reductions in PM2.5 over follow-up for a fixed baseline PM2.5 were also associated with slowed IMT progression (−2.8 µm/y [95% CI −1.6 to −3.9 µm/y] per 1 µg/m3 reduction). Study limitations include the use of a surrogate measure of atherosclerosis, some loss to follow-up, and the lack of estimates for air pollution concentrations prior to 1999.


Conclusions

This early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. These findings, even over a relatively short follow-up period, add to the limited literature on air pollution and the progression of atherosclerotic processes in humans. If confirmed by future analyses of the full 10 years of follow-up in this cohort, these findings will help to explain associations between long-term PM2.5 concentrations and clinical cardiovascular events.


Editors' Summary
Background
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, the leading cause of death among adults is coronary artery disease, a CVD in which narrowing of the heart's arteries by atherosclerotic plaques (fatty deposits that build up with age inside arteries) slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction). The fourth leading cause of death in the US is stroke, a CVD in which atherosclerotic plaques interrupt the brain's blood supply. Smoking, high blood pressure, high blood cholesterol levels, diabetes, being overweight, and being physically inactive all increase an individual's risk of developing CVD. Treatments for CVD include lifestyle changes and taking drugs that lower blood pressure or blood cholesterol levels.
Why Was This Study Done?
Another risk factor for CVD is long-term exposure to fine particulate air pollution. Fine particulate matter (PM2.5)—particles with a diameter of less than 2.5 µm or 1/30th the width of a human hair—is mainly produced by motor vehicles, power plants, and other combustion sources. Why PM2.5 increases CVD risk is unclear, but one hypothesis is that it initiates or accelerates atherosclerosis. In this prospective cohort study, which is part of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), the researchers investigate whether there is an association between long-term PM2.5 exposure and the progression of intima-medial thickness (IMT; the tunica intima and media are the innermost layers of the arterial wall) in the right common carotid artery (one of the arteries that supplies the head and neck with blood). A prospective cohort study enrolls a group of individuals and follows them to see whether exposure to certain risk factors affects their risk of developing a specific disease; progression of IMT—thickening of the arterial wall with time—in the common carotid artery is a surrogate measure of atherosclerosis.
Methods
...
Common Carotid IMT
Trained technicians captured images of the right common carotid artery from supine participants using high resolution B-mode ultrasound (Logiq 700, 13MHz; GE Medical Systems). Images collected over a distance 10 mm proximal to the common carotid bulb were transferred from each study center to the Tufts Medical Center for quantification [16]. This analysis examined the mean far wall thickness of the right common carotid, retrospectively gated to end-diastole. Blinded replicate readings gave inter-reader intra-class correlation coefficients of 0.84 and 0.86 for two separate sets of readers [17]. IMT was collected from all participants at baseline with follow-up measures collected on a subset in exam 2 and a different subset in exam 3.
Discussion
In a large prospective cohort study of adults without pre-existing cardiovascular disease, we found evidence that individuals with higher long-term residential concentrations of PM2.5 experience a faster rate of IMT progression as compared to other people within the same metropolitan area. Improvements in air quality over the duration of the study were similarly associated with changes in IMT progression, with greater reductions in PM2.5 showing slower IMT progression. These findings suggest that higher long-term PM2.5 exposures may be associated with an acceleration of vascular pathologies over time. As such, they may help explain why epidemiological studies have repeatedly found much larger associations between mortality and chronic air pollution exposures than can be explained by short-term triggering of cardiovascular events alone. Our findings furthermore bolster recent reports that falling pollution levels in the United States after the adoption of the Clean Air Act are associated with reduced mortality [25] and increased life expectancy [26],[27].
Our results indicate that persons living in residences with a 2.5 µg/m3 greater PM2.5 concentration could experience a 5.0 µm/y (95% CI 2.6–7.4 µm/y) faster rate of IMT progression than other persons in the same city. Similarly, a person who experienced a 1 µg/m3 larger reduction in PM2.5 over the follow-up period would have a 2.8 µm/y (95% CI 1.6–3.9 µm/y) slower IMT progression than another in the same city with the same baseline PM2.5. Although a recent meta-analysis [28] raises some questions as to the exact clinical implications of a larger IMT progression, results from the MESA cohort [17] suggest that participants living in parts of town with 2.5 µg/m3 higher concentrations of PM2.5 would have a 2% relative increase risk in stroke as compared to persons in a less polluted part of the metropolitan area. These findings have practical relevance since associations with IMT progression were found at concentrations commonly occurring in developed nations and well below those in developing countries. Although our mean long-term concentrations (range 10–23 µg/m3) were slightly above the new annual average US National Ambient Air Quality Standard of 12 µg/m3 and the World Health Organization guideline of 10 µg/m3, our findings are expected to hold even at lower concentrations as past evidence suggests that there is likely no safe threshold for air pollution [29].
The acceleration of atherosclerosis has been proposed as a possible mechanism linking chronic exposures to air pollution to clinical cardiovascular disease [30]32; yet this is only the second publication to investigate the longitudinal relationships between air pollution and a surrogate of atherosclerosis in humans. Our findings support the hypothesis proposed by Künzli and colleagues [33] that persons living in areas with higher long-term concentrations of PM2.5 may experience a more rapid development of vascular pathologies, which leads to the development of clinically relevant atherosclerosis at an earlier age, and increases the population at risk of cardiovascular events. Our findings that concentrations preceding baseline had slightly weaker associations with IMT progression per unit change than those during the follow-up period may indicate the importance of recent exposures or reduced exposure measurement error during the study period.
The magnitude of our findings are consistent with Künzli et al., which reported a 0.6 µm/y (95% CI −0.1 to 1.4 µm/y) larger IMT progression per 2.5 µg/m3 of PM2.5 and a 5.5 µm/y (95% CI 0.1–10.8 µm/y) larger progression for living within close proximity to a major roadway [14]. While we observed larger PM2.5 associations, the 1,483 adult participants of that collection of studies were slightly younger, more white and Hispanic, better educated, and with lower overall rates of progression than our cohort. In addition, that study used a different exposure prediction modeling approach and relied on far fewer air pollution monitors than were available to us, resulting in nearly 5 times less variable PM2.5 estimates for Los Angeles than in this investigation. Nevertheless, their PM2.5 association was well within our confidence intervals for MESA participants in Los Angeles (3.4 µm/y; 95% CI −0.002 to 6.8 µm/y per 2.5 µg/m3). Toxicological data also support our findings, with several studies documenting the growth of atherosclerotic lesions in the coronary arteries and aortas of rabbits and mice following controlled exposures to particulate matter. [2][4],[34].
We also demonstrated positive cross-sectional associations between baseline IMT and long-term exposure but these were blunted and could not be distinguished from no association after control for metropolitan area. Associations similar to our between-city results have been previously reported for long-term exposure to PM2.5 among the older adults enrolled in the Los Angeles clinical trials [8], an earlier investigation of the MESA cohort at baseline [7], and a large population-based cohort of German older adults [9]. In fact, our result of a 3–10 µm difference in IMT at baseline is very consistent with the range of 5 to 17 µm predicted by these other studies for the same unit change in PM2.5 and slightly higher than a recent investigation of young adults that reported a 2 µm larger IMT predicted per 2.5 µg/m3 [10]. Associations between air pollution and other indicators of atherosclerosis extent have been somewhat suggestive but inconsistent [7],[11][13]. Since our cross-sectional results were driven by differences in baseline IMT between the two areas with the highest (Los Angeles) and lowest (St Paul) concentrations of PM2.5, however, and were not robust to control for metropolitan area, there is the possibility of residual confounding by regional factors.
In contrast to our cross-sectional results for baseline IMT, associations with IMT progression were strongest after control for metropolitan area. The reasons for the opposite effect of site adjustment on associations with baseline IMT and IMT progression remain to be determined. Because cross-sectional associations with baseline IMT are based on between-person contrasts, these relations may be more affected by confounding by personal factors than those in our progression models, which leverage information from the same individual. Within-area associations for IMT progression showed little change with control for neighborhood socio-economic characteristics, personal education, and perceived noise and demonstrated positive associations across all six metropolitan areas in stratified analyses. Changes in concentrations over the follow-up period were also associated with IMT progression in models with and without control for metropolitan area. Thus, while some questions are raised as to the robustness of cross-sectional associations with baseline IMT, sensitivity analyses raise our confidence in the associations with IMT progression as potentially reflecting a causal association.
These data come from a well-defined prospective cohort study with an uncommonly rich set of air pollution measurements in participants' communities and homes, including individual-level perceived noise exposures. The inclusion of noise data is a unique feature of this analysis as noise has generally not been accounted for in American epidemiological studies of air pollution to date. Although noise has been independently associated with cardiovascular disease and perceived noise was related to air pollution concentrations in MESA [35],[36], interestingly, we found no evidence of confounding of the relationship between air pollution and IMT progression by perceived noise in this analysis.
Despite the many strengths of this study, this work is not without its weaknesses. First, IMT likely does not capture all of the relevant pathophysiology related to air pollution exposures [37]. Second, our exposure assignment is currently limited to predictions of pollution from ambient origin after 1999 but restriction of the analysis to non-movers (≥10 y at baseline address) did not alter our findings. Third, we did not achieve complete follow-up of all participants and data. The probability of being lost to follow-up over these first three exams was unrelated to baseline IMT levels, however, and the likelihood of missing covariate or exposure data was also unrelated to baseline IMT or IMT progression. Missing covariate information was similarly unrelated to baseline exposure concentrations. This finding suggests that bias in our primary associations due to selection is unlikely although it is always a possibility in any longitudinal study. Furthermore, we are currently not accounting for changes in neighborhood characteristics that also may have occurred during the study period. Control for time-varying vascular risk factors in our extended adjustment model, which may capture some time-varying socio-economic trends, did not substantially alter our findings so we might hypothesize that this is not a major source of confounding. The lack of an association between reductions in air pollution and changes in healthy food stores is further supportive of this hypothesis. Nevertheless, future work through MESA will address this question more thoroughly as they explore the impacts of changing neighborhoods on health. Similarly, our exposure assessment does not currently account for the penetration of outdoor particles into indoor air but correlations of outdoor and indoor PM2.5 of outdoor origin have been shown to be high [38]. Future analyses of MESA Air will confirm the findings of this early dataset using IMT data collected during MESA clinical visits 4 and 5. These analyses will furthermore incorporate estimates of air pollution infiltration into participant homes and participant time-activity information, as well as investigate other correlated pollutants that may explain some of this PM2.5 association and explore relationships with clinical events.
Overall, these results for IMT in the first three exams of a large, multi-center, population-based cohort study support the hypothesis that PM2.5 may be associated with the progression of atherosclerosis, even at levels below existing regulatory standards. Such a pathway would lend further support to reported associations between air pollution and the incidence of clinical cardiovascular disease.