CYSTIC PARATHYROID ADENOMA

Girish M Parmar, et al: Cystic Parathyroid Adenoma in Four Patients from India,

JAFES,  Vol. 27 No. 2 November 2012

 

DISCUSSION

 

Here we describe  4  cases with cystic lesions of the parathyroid gland. Three of these (Cases  1,2  and  3) had parathyroid adenomas with cystic degeneration whereas Case 4 had  a  true parathyroid cyst. Cystic lesions of the parathyroid gland are rare (0.5%–1% of all parathyroid pathologies).  Macroscopic cysts larger than 1 cm in diameter are referred to as parathyroid cysts and necessitate further investigation. Some investigators have suggested that the true prevalence of parathyroid cysts remains uncertain and that these lesions may occur more frequently than is generally appreciated.Cystic lesions of the  parathyroid gland can be  either due to true parathyroid cyst  as seen in Case 4, or due to cystic degeneration of parathyroid adenoma as seen in Cases 1, 2 and 3. Most of the parathyroid gland adenomas are solid while cystic degeneration is seen in 1-2% of patients with primary hyperparathyroidism.

 

Approximately 90% of true parathyroid cysts are classified as nonfunctioning cysts  with normal calcium concentrations  and 10% are functioning cysts  with elevated calcium concentration. However,  in one study, functioning parathyroid cysts were more common. A true parathyroid cyst needs to be differentiated from  a parathyroid adenoma with cystic degeneration. Parathyroid cysts are more frequent in females between 20 to  60 years of age,  whereas parathyroid adenomas are more common after 50 years of age.

 

Patients with true nonfunctional parathyroid cysts present with compressive symptoms. On the other hand, patients with true functional parathyroid cysts  and patients with cystic  parathyroid adenoma  present with signs and symptoms of hypercalcemia. 

 

Parathyroid cysts are of variable sizes, ranging from 1 to 10 cm in greatest dimension, with the average cyst measuring approximately 3 to 5 cm. In 85  - 90% of cases, they are located in the neck and often involve the inferior parathyroid glands. In 5 - 10% of cases they have been detected  at ectopic sites  anywhere from the angle of the mandible to the mediastinum. The mediastinal location of the parathyroid cyst can be ascribed to two factors. First, the cyst may descend into the mediastinum because of  its weight and negative intrathoracic pressure. Second, an aberrant mediastinal parathyroid gland may give rise to the cyst.  

 

 

Degeneration of an existing parathyroid adenoma secondary to hemorrhage into the adenoma, also results in cyst formation. The other different theories proposed are: (1) retention of glandular secretions, (2) persistence of vestigial pharyngobranchial ducts, (3) persistence of Kursteiner's canals, (4) enlargement of a microcyst, or (5) coalescence of the microcysts. None of these theories are

universally applicable, and the processes leading to cyst formation may well differ from one person to the next.

Ultrasonography may reveal a nonspecific cystic structure. Analysis of the aspirate generally reveals elevated PTH level, diagnostic of parathyroid cyst.Nonfunctional parathyroid cysts  have  high  fluid PTH

concentrations, in conjunction with normal serum PTH concentrations.

In functional parathyroid cysts, cystic fluid PTH levels can reach several million pg/ml.PTH levels in the cystic fluid were measured only in the fourth patient. 

 

The histologic distinction between a cystic parathyroid adenoma and the rare functional parathyroid cyst is made by the former having a preponderance of chief cells with multilocular degenerative thick-walled cysts and the latter usually consisting of a unilocular thin-walled cyst. 

 

Treatment strategies for parathyroid cysts include surgical excision or aspiration or injection of sclerosing agents.Surgical treatment seems to be the preferred intervention for functional and symptomatic parathyroid cysts as in our patient. Fine-needle aspiration yields the diagnosis and may be considered the treatment of choice for nonfunctional parathyroid cysts. It  leads  to cystic regression without recurrence.

Several reports in the literature support fine-needle aspiration as a therapeutic modality.  For recurrent  nonfunctional parathyroid cysts, sclerotherapy with use of tetracycline and alcohol has also been described. It has been effective but is associated with the risk of subsequent fibrosis and recurrent laryngeal nerve palsy.If  aspiration cannot be done safely or the cyst recurs  after successful aspiration, surgical excision should be done.

Ultrasound-Guided HIFU Used for Treatment of Breast Fibroadenomas

Ultrasound-Guided HIFU Used for Treatment of Breast Fibroadenomas

  

A new noninvasive therapeutic application using ultrasound-guided, high-intensity focused ultrasound (HIFU) is currently being employed for a specifically localized ablation with no skin damage. The ultrasound waves are focused on a small area where the rise in temperature leads to tissue necrosis. This precision avoids injuring healthy tissues around the lesion.

The echotherapy is a technique that enables clinicians to visualize and simultaneously treat a tumor such as fibroadenoma with no incision or scar.

Theraclion (Paris, France; www.theraclion.com), a specialist in cutting-edge medical technology that develops echotherapy technology that uses HIFU, has received the CE marking approval for the noninvasive treatment of breast fibroadenomas, a first for this indication.

“The CE marking widens the use of our technology in the major area of breast fibroadenoma.

Our technology can now be offered to all women suffering from this pathology in Europe. They can benefit from a noninvasive outpatient treatment without general anesthesia which puts an end to the embarrassment and anxiety triggered by this kind of tumor. Noninvasive focused ultrasound surgery guided by real-time ultrasound imaging is consistent with the logic of developing lesser invasive treatments and a reduction of health costs.

This market authorization in Europe will allow us to grow by creating noninvasive surgery centers based on our resulting echotherapy solution within leading hospitals and clinics. Other tumors beside breast fibroadenomas will be treated in a noninvasive manner in the near future,” said Jean-Yves Burel, CEO of Theraclion.

Fibroadenoma is the most widely spread breast benign tumor, with 10% of women risk developing it in their lifetime. It represents more than half of breast biopsies. This disorder hits women of all ages but is a lot more frequent with women under 30.

Estimates show that 50,000 fibroadenoma tumors are detected each year in France, with 320,000 in Europe and 640,000 in the United States.

“I used the EchoPulse to treat 11 patients during a clinical trial at the American Hospital of Paris from January to October 2012. The results from this technique are encouraging with a 60% volume reduction of fibroadenoma in an average period of six months. EchoPulse could represent an interesting alternative to classical surgery,” added Dr. Marc Abehsera from the medical imaging service at the American Hospital of Paris.

“It is interesting [to be able to] participate in the assessment of echotherapy in breast fibroadenoma in the French trial. We are hoping to participate in a multicenter trial that will measure the effects of this type of treatment in breast cancer,” stated Dr. Edouard Poncelet from the woman imaging service at the Valenciennes Hospital Center).

A clinical trial on 40 patients has shown the efficiency and the excellent tolerance of echotherapy for this type of pathology. Currently, fibroadenomas have been treated in three French centers (Lille Jeanne de Flandres Hospital, the Valenciennes Hospital, and the American Hospital of Paris) and one center in Bulgaria (the University Hospital of Sofia), with considerable volume reductions accompanied by the resolution of symptoms.

EchoPulse, the medical device developed by Theraclion, uses ultrasound imaging as a targeting system and HIFU for tissue necrosis, thereby eliminating the need for patients to undergo a surgical procedure. EchoPulse is unique as it combines in the same device an imaging monitoring and treatment system while remaining compact and mobile. In addition to its ergonomic benefits, it provides excellent image quality, a millimetric accuracy of wave shots, and an integrated cooling system for the patient’s safety. The benefits offered by EchoPulse are beneficial for the patients (non-invasive, scarless, and mobile treatment, conscious sedation) but also for the practitioners (fast, effective, and harmless) and hospital centers (efficient, less hospitalization costs, one device for several pathologies).

SIÊU ÂM THEO DỎI GAN GHÉP

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Liver Transplantation

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ELASTO ULTRASOUND and LIVER FIBROSIS / EASL 2013 NETHERLANDS

AMSTERDAM -- Although biopsy remains the gold standard for diagnosing liver fibrosis, imaging tests increasingly appear to be a viable way to garner equivalent information with less patient discomfort and risk, researchers said here. In presentations at the meeting of the European Association for the Study of the Liver, scientists from across Europe reported on the strengths and weaknesses of various imaging modalities as tools for routine clinical practice. There was no clear winner among transient elastography, magnetic resonance elastography (MRE), real-time shear wave elastography (RTSWE), and acoustic radiation force impulse (ARFI) imaging, but all appeared to be nearly as accurate as liver biopsy in quantitative assessment of fibrosis and for predicting outcomes such as death and cirrhotic decompensation. The role of liver imaging for these purposes in the U.S. has recently come to the fore with the FDA's clearance last week of the Fibroscan transient elastography device. Fibroscan is the established leader in noninvasive fibrosis imaging and, according to its French manufacturer, Echosens, the U.S. is the last major market to approve its device. All these forms of elastography work by setting up shear waves in the liver. Patterns of propagation of these waves correspond to the degree of liver stiffness, which in turn correlates with the level of fibrosis. All but MRE use ultrasound to generate the waves. Studies presented here evaluated one or more of these technologies against another, with or without liver biopsy as a reference standard, and in a variety of patient populations.

Transient Elastography Versus Biopsy

Perhaps the most direct assessment was reported by Juan Macias, MD, of Hospital Universitario de Valme in Seville, Spain. He reported a retrospective analysis of 297 patients coinfected with HIV and hepatitis C virus (HCV) who had been tested with liver biopsy as well as transient elastography, with these tests performed within a year of each other. The study period covered 2005 to 2011. Findings indicated that fibrosis stage as established from biopsies and liver stiffness measurements from transient elastography were equally accurate in predicting overall mortality and decompensation of cirrhosis. Kaplan-Meier curves for patients with stage F4 fibrosis (overt cirrhosis) and for those with elastography measurements in the highest quintile (21 kPa and above) were nearly identical through up to 6 years of follow-up, for both all-cause death and for decompensation of cirrhosis, Macias reported. Point estimates of the increased risk for these outcomes were somewhat higher in models based on biopsy findings than in the elastography-based analyses, but the error bars in the latter were markedly smaller. For example, the risk of decompensation doubled with each increase in fibrosis stage (hazard ratio 2.00, 95% CI 1.32 to 3.00), whereas each 5-kPa increase in liver stiffness corresponded to a hazard ratio of 1.42 (95% CI 1.31 to 1.55). "The noninvasive nature of [transient elastography] should favor its use instead of liver biopsy when the only issue is predicting the clinical outcome of liver disease in HIV-HCV coinfection," Macias told attendees.

ARFI Versus Transient Elastography

Acoustic radiation force impulse imaging is another up-and-coming imaging method for liver disease. Like transient elastography, it uses ultrasound to generate mechanical waves within the liver, but the nature of the waves and the interpretation of the resultant patterns differs. Derek Bardou of CHU Angers in Angers, France, noted that the two technologies have been compared head-to-head in previous studies, with pooled data suggesting that ARFI is less accurate. But transient elastography has a significant drawback -- it doesn't work on obese patients. Bardou pointed out that the previous analyses were all conducted on a per-protocol basis, such that patients for whom the transient elastography attempt failed to yield usable results were excluded. He argued that a more stringent "intent-to-diagnose" analysis would be a better reflection of the utility of the two methods in routine practice. From 2009 to early 2013, he and his colleagues used both methods on a total of 267 patients with chronic, noncancerous liver disease (patients with cirrhotic complications or sepsis were excluded) who also underwent liver biopsies. Areas under the receiver-operating characteristic (AUROC) curves for classifying patients' liver disease stage were calculated for both test types, with biopsy results serving as the reference standard. The researchers found that, on a per-protocol basis, AUROC values with ARFI were indeed lower -- indicating poorer accuracy -- than those seen with transient elastography. In this analysis, Bardou and colleagues excluded 6.7% of patients in whom transient elastography could not be performed. ARFI failed in fewer than 1%. But in the intent-to-diagnosis analysis involving all 267 patients, there was no significant difference in AUROC values for the two methods. Bardou added that whole-liver results with ARFI were more accurate than findings only in the right lobe, the "classical" way to perform ARFI, he explained. RTSWE Versus Transient Elastography Versus Biopsy Another study reported here sought to validate real-time shear wave elastography as an alternative -- not necessarily superior -- to liver biopsy. Giovanna Ferraioli, MD, of Italy's University of Pavia, presented findings from 88 patients with chronic liver disease of varied origin and 33 healthy controls. Patients underwent both RTSWE (using the ElastPQ system) and transient elastography as well as biopsy. The controls had only the noninvasive testing. RTSWE, in this study, involved a fixed "sample box" located a maximum of 70 mm below the Glisson's capsule within the liver. Patients held their breath for 2 to 4 seconds and 10 images were collected, with the median stiffness value in kPa used as the final result. As the name suggests, and unlike transient elastography, RTSWE delivers readings almost immediately. In some studies, it has appeared to be more accurate as well. Both imaging methods showed stiffness values that progressed upward with the degree of fibrosis ascertained with the biopsies. RTSWE yielded somewhat more detail, in that the median values for each patient group stratified according to fibrosis stage (F0/1 to F4) tracked steadily higher. Transient elastography results for patients with F2 fibrosis, on the other hand, were nearly identical to those with F0/1 disease (5.45 versus 5.5 kPa). Ferraioli and colleagues found that, as expected, RTSWE values in the healthy controls were lower than in patients with liver disease (median 3.3 kPa, interquartile range 3.7 to 4.0). Transient elastography readings tended to be higher (median 3.8 kPa, interquartile range 4.5 to 5.0) and overlapped in the controls with those from patients with liver disease (median in F2 patients 5.45, interquartile range 4.3 to 8.0). RTSWE "compares favorably" with transient elastography, Ferraioli concluded.

MR Elastography Versus Biopsy

Use of MRI equipment to analyze liver stiffness is an even newer approach. It, too, can be used to generate vibrations that propagate through the liver. Rocio Gallego-Duran, also of the Hospital Universio de Valme, reported on a validation study in which artificial neural networks were used to generate elastography values from MRI scans. Her study involved 63 patients with biopsy-confirmed non-alcoholic fatty liver disease, including 32 with non-alcoholic steatohepatitis (NASH) and 25 with significant fibrosis. The first 22 of these patients were used as a "training cohort" for fine-tuning the software settings to match biopsy results as closely as possible. The resulting model was then tested in the remaining 41 patients, serving as a validation cohort. For diagnosing NASH, the model showed sensitivity of 77% and specificity of 90%, Gallego-Duran reported. Positive and negative predictive values were 89% and 79%, respectively. The model was not quite as good at diagnosing fibrosis. With the best-performing cutoff values, sensitivity was 87% but specificity was only 63%. As a result, the positive predictive value was just 59%, although the negative predictive value was a respectable 89%. Gallego-Duran told attendees that the MRI-based technique holds some potential advantages over the ultrasound-based methods. Because it produces high-resolution images of the entire liver, it may provide a fuller picture of liver disease and can also reveal other types of liver injury. Patients' body fat also is not an issue for image quality, as it is for transient elastography, she said.

None of the studies had commercial funding.

All of the presenters declared that they had no relevant financial interests.

Primary source: European Association for the Study of the Liver Source reference: Macias J, et al "Performance of liver stiffness compared with liver biopsy to predict survival and decompensations of cirrhosis among HIV/HCV-coinfected patients" EASL 2013; Abstract 20.

Additional source: European Association for the Study of the Liver Source reference: Bardou D, et al "First intention-to-diagnose comparison of ARFI and Fibroscan in chronic liver diseases" EASL2013; Abstract 15. Additional source: European Association for the Study of the Liver Source reference: Ferraioli G, et al "Performance of ELASTPQ® shear wave elastography technique for assessing fibrosis in chronic viral hepatitis" EASL 2013; Abstract 16.

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US in Tropical disease

 

http://www.kosmos-design.co.uk/EFSUMB-ECB/ecb-ch26-tropicaldiseases.pdf

 

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.

______________________________________

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.

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.

Sinh nhật lần thứ 60 của DNA, Nguyễn văn Tuấn

Ít 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. 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”). 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. 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. 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. 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.