terça-feira, 31 de janeiro de 2012

Células da pele dão Origem a precursores de neurônios


Scientists turn skin cells into neural precusors, bypassing stem-cell stage
Tuesday, January 31, 2012


Stem cells
Mouse skin cells can be converted directly into cells that become the three main parts of the nervous system, according to researchers at the Stanford University School of Medicine. The finding is an extension of a previous study by the same group showing that mouse and human skin cells can be directly converted into functional neurons.
The multiple successes of the direct conversion method could refute the idea that pluripotency (a term that describes the ability of stem cells to become nearly any cell in the body) is necessary for a cell to transform from one cell type to another. Together, the results raise the possibility that embryonic stem cell research and another technique called "induced pluripotency" could be supplanted by a more direct way of generating specific types of cells for therapy or research.
This new study, which will be published online Jan. 30 in the Proceedings of the National Academy of Sciences, is a substantial advance over the previous paper in that it transforms the skin cells into neural precursor cells, as opposed to neurons. While neural precursor cells can differentiate into neurons, they can also become the two other main cell types in the nervous system: astrocytes and oligodendrocytes. In addition to their greater versatility, the newly derived neural precursor cells offer another advantage over neurons because they can be cultivated to large numbers in the laboratory — a feature critical for their long-term usefulness in transplantation or drug screening.
In the study, the switch from skin to neural precursor cells occurred with high efficiency over a period of about three weeks after the addition of just three transcription factors. (In the previous study, a different combination of three transcription factors was used to generate mature neurons.) The finding implies that it may one day be possible to generate a variety of neural-system cells for transplantation that would perfectly match a human patient.
"We are thrilled about the prospects for potential medical use of these cells," said Marius Wernig, MD, assistant professor of pathology and a member of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "We've shown the cells can integrate into a mouse brain and produce a missing protein important for the conduction of electrical signal by the neurons. This is important because the mouse model we used mimics that of a human genetic brain disease. However, more work needs to be done to generate similar cells from human skin cells and assess their safety and efficacy."
Wernig is the senior author of the research. Graduate student Ernesto Lujan is the first author.
While much research has been devoted to harnessing the pluripotency of embryonic stem cells, taking those cells from an embryo and then implanting them in a patient could prove difficult because they would not match genetically. An alternative technique involves a concept called induced pluripotency, first described in 2006. In this approach, transcription factors are added to specialized cells like those found in skin to first drive them back along the developmental timeline to an undifferentiated stem-cell-like state. These "iPS cells" are then grown under a variety of conditions to induce them to re-specialize into many different cell types.
Scientists had thought that it was necessary for a cell to first enter an induced pluripotent state or for researchers to start with an embryonic stem cell, which is pluripotent by nature, before it could go on to become a new cell type. However, research from Wernig's laboratory in early 2010 showed that it was possible to directly convert one "adult" cell type to another with the application of specialized transcription factors, a process known as transdifferentiation.
Wernig and his colleagues first converted skin cells from an adult mouse to functional neurons (which they termed induced neuronal, or iN, cells), and then replicated the feat with human cells. In 2011 they showed that they could also directly convert liver cells into iN cells.
"Dr. Wernig's demonstration that fibroblasts can be converted into functional nerve cells opens the door to consider new ways to regenerate damaged neurons using cells surrounding the area of injury," said pediatric cardiologist Deepak Srivastava, MD, who was not involved in these studies. "It also suggests that we may be able to transdifferentiate cells into other cell types." Srivastava is the director of cardiovascular research at the Gladstone Institutes at the University of California-San Francisco. In 2010, Srivastava transdifferentiated mouse heart fibroblasts into beating heart muscle cells.
"Direct conversion has a number of advantages," said Lujan. "It occurs with relatively high efficiency and it generates a fairly homogenous population of cells. In contrast, cells derived from iPS cells must be carefully screened to eliminate any remaining pluripotent cells or cells that can differentiate into different lineages." Pluripotent cells can cause cancers when transplanted into animals or humans.
The lab's previous success converting skin cells into neurons spurred Wernig and Lujan to see if they could also generate the more-versatile neural precursor cells, or NPCs. To do so, they infected embryonic mouse skin cells — a commonly used laboratory cell line — with a virus encoding 11 transcription factors known to be expressed at high levels in NPCs. A little more than three weeks later, they saw that about 10 percent of the cells had begun to look and act like NPCs.
Repeated experiments allowed them to winnow the original panel of 11 transcription factors to just three: Brn2, Sox2 and FoxG1. (In contrast, the conversion of skin cells directly to functional neurons requires the transcription factors Brn2, Ascl1 and Myt1l.) Skin cells expressing these three transcription factors became neural precursor cells that were able to differentiate into not just neurons and astrocytes, but also oligodendrocytes, which make the myelin that insulates nerve fibers and allows them to transmit signals. The scientists dubbed the newly converted population "induced neural precursor cells," or iNPCs.
In addition to confirming that the astrocytes, neurons and oligodendrocytes were expressing the appropriate genes and that they resembled their naturally derived peers in both shape and function when grown in the laboratory, the researchers wanted to know how the iNPCs would react when transplanted into an animal. They injected them into the brains of newborn laboratory mice bred to lack the ability to myelinate neurons. After 10 weeks, Lujan found that the cells had differentiated into oligodendroytes and had begun to coat the animals' neurons with myelin.
"Not only do these cells appear functional in the laboratory, they also seem to be able to integrate appropriately in an in vivo animal model," said Lujan.
The scientists are now working to replicate the work with skin cells from adult mice and humans, but Lujan emphasized that much more research is needed before any human transplantation experiments could be conducted. In the meantime, however, the ability to quickly and efficiently generate neural precursor cells that can be grown in the laboratory to mass quantities and maintained over time will be valuable in disease and drug-targeting studies.
"In addition to direct therapeutic application, these cells may be very useful to study human diseases in a laboratory dish or even following transplantation into a developing rodent brain," said Wernig.
###
Stanford University Medical Center: http://med-www.stanford.edu/MedCenter/MedSchool

terça-feira, 24 de janeiro de 2012

IPhone nas escolas médicas


No Lancet deste mes saiu essa informação sobre o papel do IPhone

“People want to use it, and it's easy to carry around.” Gareth Frith, Technology Enhanced Learning Manager at the University of Leeds, UK, is talking about the device that is changing the delivery of medical education at his institution: the Apple iPhone. His department's interest in mobile information technology goes back around 5 years. UK medical courses often involve attachments in district hospitals and whilst Gareth saw that smartphones could help students studying remotely, his initial work showed that “it was fairly obvious that the ideas were right, but the technology at that point wasn't up to the task”.
The iPhone changed everything. The medical school uses it in two main ways. The first is as an information resource. Students are given electronic copies of clinical handbooks and the British National Formulary. In the modern age, when white coats and their accompanying deep pockets are becoming a distant memory, this is an important function in itself. However, it's the second use—to support clinical learning—that I find most interesting. Gareth tells me that a dedicated app allows students to upload reflections on cases they have seen (with sensitive information removed) to an online portfolio in real time. Workplace-based assessments can also be completed on the spot by clinicians: in short, the iPhone is helping the medical school to provide consistent support for students, and to get them into good habits for the future: “The biggest challenge we've got as educators is to convince people to do things now rather than get to the point when they're applying for revalidation, and think ‘I wish I'd done that earlier.’ Because you can't actually go back and recapture that information.”
All fourth and fifth year medical students at Leeds are now issued with iPhones. They are given the option of adding pay-as-you-go texts and calls. Student response is generally positive: the teachers are more mixed in their views. Gareth thinks that the advanced voice interface on the iPhone 4S may help with acceptability to clinicians, since they will be able to dictate feedback rather than type it. As for the future, Gareth is developing educational use of the iPad and also dealing with a less technical, but no less important issue: “People are slightly sceptical about why a student is carrying an iPhone, so we've had some iPhone cases made, which say something like ‘Leeds University School of Medicine: This is a tool for my MBChB’. So they can turn it round and show people that it's not a toy or a personal device.” Where Leeds has gone, I suspect others will soon follow.

terça-feira, 17 de janeiro de 2012

Tb resistente a todas Drogas Informe WHO


Tuberculosis that is “resistant to all drugs”

Frequently asked questions

January 2012
What is “totally drug resistant” tuberculosis (“TDR-TB”)?
In 2006, the first reports of extensively drug-resistant tuberculosis (XDR-TB), an even more severe form of drug resistant TB than multidrug-resistant TB (MDR-TB), began to appear. [1,2] MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other first-line drugs (FLD). XDR-TB is defined as resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin, and kanamycin). Within a year of the first reports of XDR-TB, isolated cases were reported in Europe that had resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested.[3,4,5] In 2009, a cohort of 15 patients in Iran was reported which were resistant to all anti-TB drugs tested.[6]

The terms “extremely drug resistant” (“XXDR-TB”) and “totally drug-resistant TB” (“TDR-TB”) were given by the respective authors reporting this group of patients. Recently, a further 4 patients from India with “totally drug resistant” tuberculosis (“TDR-TB”) were described [7], with subsequent media reports of a further 8 cases.[8]


To submit questions
please click here
Is the term “totally drug resistant” clearly defined? Is it recognised by the WHO?
The term “totally drug resistant” has not been clearly defined for tuberculosis. While the concept of “total drug resistance” is easily understood in general terms, in practice, in vitro drug susceptibility testing (DST) is technically challenging and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied and consensus reached on appropriate methods, critical drug concentrations that define resistance, and reliability and reproducibility of testing.[9] Data on the reproducibility and reliability of DST for the remaining SLDs are either much more limited or have not been established, or the methodology for testing does not exist. Most importantly, correlation of DST results with clinical response to treatment has not yet been adequately established. Thus, a strain of TB with in vitro DST results showing resistance could in fact, in the patient, be susceptible to these drugs. The prognostic relevance of in vitro resistance to drugs without an internationally accepted and standardised drug susceptibility test therefore remains unclear and current WHO recommendations advise against the use of these results to guide treatment.[10]

Lastly, new drugs are under development, and their effectiveness against these “totally drug resistant” strains has not yet been reported.

For these reasons, the term “totally drug resistant” tuberculosis is not yet recognised by the WHO. For now these cases are defined as extensively drug resistant tuberculosis (XDR-TB), according to WHO definitions.

How easily do MDR or XDR-TB or “TDR-TB” spread?
TB bacilli with different levels of resistance spread in the same way and with the same risk of infection as fully drug susceptible strains. For more information please click here.

What does the WHO recommend should be done to address MDR or XDR-TB?
The discovery of patients with MDR or XDR-TB emphasizes the importance of ensuring that all care for tuberculosis, whether in the public or private sector, must conform to international standards[11] in order to prevent the emergence of drug resistance. Almost all countries must, in addition, ensure appropriate diagnosis and treatment of cases of MDR-TB.[11,12] National regulations for the quality and dispensing of anti-TB drugs, particularly of the second-line drugs, need to be strictly enforced.

To achieve this, most countries require simultaneous scale-up of the diagnostic and treatment services for drug-resistant TB, and the provision of adequate and continuous supplies of quality assured SLDs for both MDR- and XDR-TB to meet the increased demand.

MDR and XDR-TB raise many difficult issues concerning the management of patients, for example, whether to isolate patients, the need for institutional, palliative or end-of-life care, and the compassionate use of new drugs. The reader is referred to the WHO’s Guidelines for the programmatic management of drug-resistant tuberculosis.[10]

Are there any treatment options for patients with XDR-TB?
XDR-TB severely reduces the options for treatment, but, yes, there are still options available, although they have not been studied in large cohorts. For such cases additional drugs will need to be procured from among the group of agents that are known to have some action against tuberculosis but are not routinely recommended for treatment of MDR-TB.[10] These include clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, imipenem/cilastatin, clarithromycin and high-dose isoniazid. Efficacy is not assured, however, and both toxicity and cost for some of these compounds are high. Potential purchasers should be aware that international availability of some of these agents is limited at present.

Will the new drugs in development soon be available for treatment of XDR-TB?
Several new drugs belonging to new classes of anti-mycobacterial agents are under development, but until they are shown to be effective in properly conducted clinical trials, WHO cannot recommend their routine use. In particular WHO advises strongly against simply adding a single new drug to a failing regimen. The use of experimental drugs outside clinical trials (compassionate use) has been addressed by the WHO.[10]

What strategies underlie WHO’s recommendations for dealing with drug resistance?
The WHO-recommended Stop TB Strategy provides the framework for the effective large-scale treatment and control of both drug-susceptible and drug-resistant disease.[13] The Global Plan to Stop TB, 2011 – 2015, developed by the Stop TB Partnership, including WHO, estimates funding needs for implementation levels needed to achieve global targets.[14] Critical weaknesses in many countries’ current capacity and approaches to the treatment and control of MDR-TB and XDR-TB have been identified and the policy approaches necessary to address them have been described.[15]

Are countries aware of the need to respond to drug resistant TB? How are they doing?
In 2009, the Beijing Call for Action[17] and the approval of the World Health Assembly Resolution 62.15 [17], with 193 Member States present, signalled a step forward in countries’ commitment to, and planning for, the treatment and control of MDR-TB. Planning, funding, and implementation have, however, fallen behind the milestones that were set. In 2010, only 20 out of 36 countries with a high burden of TB or MDR-TB had at least one laboratory capable of performing TB culture and DST per 5 million people. Much of Africa and the Indian subcontinent remain poorly served. Globally in 2010, only 4% of new and 6% of previously treated TB patients were reportedly tested for susceptibility to isoniazid and rifampicin, while the Global Plan targets are 20% or more, and 100%, respectively. The number of reported cases of MDR-TB was only 18% of the estimated number of cases among TB patients notified in 2010. And only around one quarter of them were treated in accordance with recommended international guidelines. Data (unpublished) collected by WHO show that just over a half of MDR-TB patients in recent cohorts completed their treatment successfully, and among patients with XDR-TB, death is more common than successful treatment; default and treatment failure rates are also high.

Are sufficient financial resources available in countries to address MDR-TB?
According to the 2011 WHO Global TB report, funding for MDR-TB in 2011 was US$0.7 billion, US$ 0.2 billion less than the need estimated in the Global Plan to Stop TB.[18] Of the reported funding, US$ 0.5 billion (71%) was accounted for by three upper-middle income countries: Kazakhstan, the Russian Federation and South Africa. The funding required for MDR-TB to reach the 2015 target of universal access to care rises from US$ 0.9 billion in 2011 to US$ 2 billion in 2015; most of this funding is needed in middle-income countries. Thus, much more funding needs to be mobilized in high MDR-TB burden countries to ensure proper diagnosis and treatment.

What measures will be taken by the WHO at the global level, to address “TDR-TB” specifically?
To facilitate discussion and to make surveillance consistent, an initial step is for WHO and partners to develop a consensus on whether a new definition is needed, and if so what the term and definition should be for such patients, taking into account the technological limitations of DST that still exist in 2011. If “totally drug-resistant” TB defines a subset of XDR-TB with different characteristics to other XDR-TB cases, particularly with respect to the outcome of such cases, then an internationally recognised definition may be needed. This should be seen as a call for national TB programmes and research groups to make data available on the outcomes of all highly resistant cases.

WHO is organising an Expert Group Meeting in March, 2012 to assess additional data on DST accuracy obtained since 2008. This meeting will be expanded to include a consultation on possible definitions for “totally drug-resistant” TB. WHO is also convening another Expert Group Meeting in March to assess the latest evidence behind a new molecular line probe assay for detecting XDR-TB.

For more information, please contact:
Monica Dias
Stop TB Department
WHO/Geneva
Email: diash@who.int

References

1.Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs worldwide. MMWR Morb Mortal Wkly Rep 2006; 55: 301-305.
2.World Health Organization (WHO). Extensively drug-resistant tuberculosis (XDR.TB): recommendations for prevention and control. Weekly Epidemiol Record 2006; 81: 430-432.
3.GB Migliori, R Loddenkemper, F Blasi and MC Raviglione. 125 years after Robert Koch’s discovery of the tubercle bacillus: the new XDR-TB threat. Is “science” enough to tackle the epidemic? Eur Respir J 2007; 29: 423-427.
4.Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveil. 2007; 12(20): pii=3194.
5.Migliori GB, Ortmann J, Girardi E et al. Extensively drug-resistant tuberculosis, Italy and Germany. Emerging Infectious Diseases, 2007;13: 780-782.
6.Velayati AA, Masjedi MR, Farnia P, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis of totally drug-resistant strain in Iran. Chest 2009; 136: 420-425.
7.Zarir F Udwadia, Rohot A Amale, Kanchan K Ajbani, Camilla Rodrigues. Correspondence: Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis, published online December 21, 2011 doi:10.1093/cid/cir889
8.Times of India. New deadlier form of TB hits India. Jan 7, 2012.
9.World Health Organization. Policy guidance on drug susceptibility testing (DST) of second-line anti-tuberculosis drugs. WHO/HTM/TB/2008.392
10.WHO. Guidelines for the programmatic management of drug-resistant tuberculosis: Emergency Update 2008. WHO/HTM/TB/2008.402. Geneva, Switzerland: WHO, 2008.
11.The Tuberculosis Coalition for Technical Assistance. International Standards of Care. 2006. http://www.who.int/tb/publications/2006/istc_report_shortversion.pdf (accessed 12 January 2012)
12.WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2011 Update. WHO/HTM/TB/2011.6. Geneva, Switzerland: WHO, 2011.
13.Raviglione MC, Uplekar MW. WHO’s new Stop TB Strategy. Lancet 2006; 367: 952-5.
14.Stop TB Partnership. The Global Plan to Stop TB 2011-2015: transforming the fight towards elimination of tuberculosis. Geneva, World Health Organization, 2010 (WHO/HTM/STB/2010.2).
15.Nathanson E, Nunn P, Uplekar MW, Floyd K, Jaramillo E, Lönnroth K, Weil D, and Raviglione M. MDR Tuberculosis — Critical Steps for Prevention and Control. N Engl J Med 2010; 363: 1050-8.
16.WHO. A ministerial meeting of high M/XDR-TB burden countries. WHO/HTM/TB/2009.415. Geneva, Switzerland: WHO, 2009. (Accessed 12 January 2012)
17.WHO. 62nd World Health Assembly. Prevention and control of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. WHA62.15. 8th plenary meeting, May 22, 2009. A62/VR/8. http://www.who.int/tb/features_archive/wha62_15_tb_resolution/en/index.html. (Accessed 12 January 2012)
18.WHO. Global Tuberculosis Control 2011. WHO/HTM/TB/2011.16. Geneva, Switzerland: WHO, 2011.

13 January 2012

Frequently Asked Questions
PDF version
pdf, 465kb

segunda-feira, 16 de janeiro de 2012

NEJM Caso Clínico Patológico - Jan 12, 2012

Case 1-2012 — An 82-Year-Old Man with Persistent Ulcers on the Hands

Daniela Kroshinsky, M.D., Mai P. Hoang, M.D., and Robert P. Hasserjian, M.D.
N Engl J Med 2012; 366:166-174 


http://www.nejm.org/doi/pdf/10.1056/NEJMcpc1104568Article
 
References

Presentation of Case

Dr. Sarah Gee (Dermatology): An 82-year-old man was admitted to this hospital because of persistent skin lesions on the hands. The patient had a history of diabetes mellitus and recurrent hidradenitis suppurativa. Five weeks before admission, he was admitted to another hospital because of drainage from a perineal abscess that was unresponsive to cephalexin. On examination, he reportedly had a small abrasion on his left hand, which he thought was caused by a dog bite. The administration of cephalexin was discontinued, and piperacillin–tazobactam and vancomycin were begun. During the following week, increasing erythema and an enlarging hemorrhagic bulla developed on the dorsum of the left hand and a diffuse, urticarial, and purpuric rash developed on the torso. Laboratory testing reportedly revealed thrombocytopenia. Débridement of the lesion of the left hand was performed; pathological examination of a specimen reportedly showed acute inflammation and granulation tissue. After débridement, the lesion worsened and similar lesions developed on the right hand, on the metacarpophalangeal joints. The lesions were reportedly painful to the touch and to manipulation, with ulceration extending to the tendons. Glucocorticoids were administered. On the 10th hospital day, a biopsy specimen of the skin of the right abdomen was obtained; pathological examination reportedly showed leukocytoclastic vasculitis and no microorganisms. The administration of piperacillin–tazobactam and vancomycin was stopped, as was subcutaneous heparin (begun during admission), and ciprofloxacin and linezolid were begun, in conjunction with a topical antimicrobial solution for the hands. The lesions expanded to include the proximal interphalangeal joints and became more erosive and painful. On the 13th day, the patient was transferred to a second hospital for evaluation and management of the skin lesions. At the second hospital, the patient reported weight loss of approximately 2.3 kg per week during the previous month and intermittent diarrhea. On examination, the temperature was normal. On the dorsal surfaces of the hands were well-demarcated, edematous, friable, erythematous-to-violaceous plaques, with gray discoloration at the margins (Figure 1AFigure 1Clinical Photographs of the Patient.). Smaller violaceous, erythematous, edematous plaques were present on the trunk and thighs. A biopsy specimen of the skin on the dorsum of the right hand was obtained; pathological examination revealed a superficial and deep, dense, diffuse neutrophilic infiltrate. Staining for microorganisms was negative, and cultures were sterile. The serum level of sodium was 130 mmol per liter (reference range, 135 to 145), and levels of the other electrolytes were normal. Tests of liver function were normal, and testing for antibodies to the platelet factor 4–heparin complex was negative; other test results are shown in Table 1Table 1Laboratory Data.. The administration of antibiotics was stopped, higher-dose systemic glucocorticoids were begun, and local wound care was performed, with partial improvement. The patient was discharged home on the fifth day, taking prednisone (70 mg orally daily) with instructions to initiate a taper in 2 to 3 weeks. He also was prescribed an intensive wound-care regimen, with the assistance of a home nurse. Shortly after discharge, the prednisone dose was tapered from 70 mg daily to 40 mg daily, the administration of cyclosporine (300 mg daily) was begun, and intralesional triamcinolone acetonide (to a total of 60 mg daily) was injected. Six days before admission to this hospital, a biopsy specimen of the skin on the dorsum of the right hand was obtained; pathological examination reportedly revealed neutrophilic dermatitis, with a suggestion of follicular perforation and folliculitis; no microorganisms were seen. The next day, levels of serum electrolytes, total bilirubin, total protein, globulin, and calcium were normal, as were tests of liver function; other laboratory-test results are shown in Table 1. Three days later, the lesions seemed improved; the cyclosporine dose was decreased to 100 mg orally daily, dapsone (100 mg daily) was started, and prednisone was maintained at 40 mg daily. During the next 2 days, the lesions on the patient's hands worsened. He was referred to this hospital and admitted because of increased pain and oozing of the lesions. The patient reported feeling well except for his hands. He had a history of hidradenitis suppurativa, with recurrent abscesses, for more than 20 years, for which multiple antibiotics had been administered; diabetes mellitus, for which he had recently started taking insulin; hypertension; hyperlipidemia; cholelithiasis; a malignant melanoma of the back, which had been excised; macrocytic anemia with low folate levels; multinodular goiter; diverticulosis; microhematuria; chronic obstructive pulmonary disease; bradycardia, for which a cardiac pacemaker had been inserted; and bilateral leg edema. He had had herniorrhaphies and an appendectomy. Other medications included lisinopril and aspirin. He was allergic to penicillin. He was retired, lived with his wife, smoked cigarettes, and drank alcohol in moderation. He had no history of exposures to chemicals. There was no family history of similar skin lesions, autoimmune disorders, or inflammatory bowel disease. On examination, the respiratory rate was 30 breaths per minute and the oxygen saturation was 97% while the patient was breathing ambient air; other vital signs were normal. There were violaceous, edematous, denuded plaques on the metacarpophalangeal joints of both hands and on both elbows (Figure 1B), as well as bilateral leg edema. The serum iron level was 50 μg per deciliter (9 μmol per liter; reference range, 45 to 160 μg per deciliter [8 to 29 μmol per liter]), iron-binding capacity 220 μg per deciliter (39 μmol per liter; reference range, 228 to 429 μg per deciliter [41 to 77 μmol per liter]), and ferritin level 540 ng per milliliter (reference range, 30 to 300, in men). The serum levels of electrolytes, calcium, magnesium, phosphorus, total protein and globulin, free thyroxine, lactate dehydrogenase, vitamin B12, folate, and glucose-6-phosphate dehydrogenase were normal, as were tests of liver function. Testing was negative for rheumatoid factor; evidence of hepatitis A, B, and C viruses; antiphospholipid antibodies; and lupus anticoagulant. Other test results are shown in Table 1. The administration of trimethoprim–sulfamethoxazole was begun. No Bence Jones proteins were detected in a concentrated urine specimen. Urinalysis revealed cloudy yellow urine, trace protein, 3+ occult blood, 20 to 50 red cells per high-power field, and 3 to 5 hyaline casts per low-power field. On the fourth day, a diagnostic procedure was performed.

Differential Diagnosis

Dr. Daniela Kroshinsky: I am aware of the diagnosis in this case. This patient presented with a violaceous bullous lesion on the hand after a possible dog bite. The lesion expanded on débridement, and new lesions arose on the other hand. The cutaneous findings were accompanied by diarrhea and weight loss, but the patient was otherwise asymptomatic. The process was initially thought to be consistent with a necrotizing hemorrhagic cellulitis. The differential diagnosis that I would consider for these ulcerative, bullous, necrotic hand lesions includes infection (bacterial, mycobacterial, protozoal, fungal, or viral); a vasculitis (e.g., vasculitis associated with antineutrophil cytoplasmic antibodies [ANCA] or vasculitis of medium-size vessels); and neutrophilic dermatoses (e.g., pyoderma gangrenosum or Sweet's syndrome). Other blistering processes that often affect the hands but are not clinically consistent with this patient's presentation are porphyria cutanea tarda and epidermolysis bullosa acquisita.

Infection

An infectious cause of the initial ulceration should be considered in view of the history of a dog bite, which can transmit several types of infectious organisms. The differential diagnosis would include bacterial infections (e.g., necrotizing cellulitis), mycobacterial infections (e.g., Mycobacterium ulcerans), protozoal infections (e.g., leishmaniasis), deep fungal infections (e.g., sporotrichosis), and viral infections (e.g., orf). Most of these causative agents are not endemic in the northeastern United States, and this patient reported no recent or remote travel to areas where they are endemic. The main bacterial infections to consider in association with dog bites are from staphylococci, streptococci, anaerobes, and pasteurella species. The aggressive nature of this patient's initial lesion also requires consideration of more aggressive organisms, such as clostridium. Many cases of necrotizing cellulitis result from local trauma and are more often seen in patients with a history of diabetes, which this patient has. Despite the pathological diagnosis of necrotizing cellulitis, there was no crepitus on examination of the patient or gas on imaging, although this finding is not seen in all forms of necrotizing cellulitis. He had no other signs of infection (e.g., fever or leukocytosis), he had no response to broad-spectrum antibiotics, cultures of the lesion were sterile, and his lesions worsened with débridement; in addition, lesions developed in nontraumatized areas in the absence of signs of systematized infection. For these reasons, infection seemed unlikely.

Vasculitis

Certain forms of vasculitis can cause deep, painful ulceration, particularly vasculitis of medium-size vessels and the ANCA-associated forms of vasculitis. These were less likely diagnoses in this patient because of the previous biopsy specimen that lacked evidence of vasculitis, the absence of respiratory symptoms that would suggest necrotizing granulomatous inflammation of the upper and lower respiratory tracts, and the glomerulonephritis that would be present in Wegener's granulomatosis. The peak age at onset of this condition is 45 to 65 years, younger than this patient. Cutaneous polyarteritis nodosa is a condition of necrotizing vasculitis of medium-size vessels that is limited to the skin. It would be unlikely in this patient, since a manifestation is painful nodules that subsequently ulcerate, predominantly on the legs. Additional findings in cases of cutaneous polyarteritis nodosa include fever, myalgias, arthralgias, peripheral neuropathy, livedo reticularis, and atrophie blanche, all of which were absent in this patient. Repeat biopsy with close attention to any blood-vessel abnormalities and levels of cytoplasmic ANCA and perinuclear ANCA would help to rule out these forms of vasculitis.

Neutrophilic Dermatoses

Pathergy

The patient's original lesion appeared to arise after minor skin trauma, and during the hospital stay, he had evidence of new skin lesions arising at sites of iatrogenic skin trauma. This phenomenon, known as pathergy, is an inflammatory response that develops after intradermal trauma and is manifested as erythematous-to-violaceous papules, plaques, and pustules, sometimes with secondary ulceration. A diagnostic test for pathergy is often used to confirm a suspicion of Behçet's disease — an 18-gauge needle is inserted at an angle through the dermis, and the appearance of lesions within 48 hours after insertion is indicative of a positive test. Pathergy occurs not only in Behçet's disease but also in acute febrile neutrophilic dermatosis (Sweet's syndrome), pyoderma gangrenosum, bowel-associated dermatosis–arthritis syndrome, and rheumatoid arthritis. I most often see pathergy associated with these conditions as an incidental finding on physical examination, manifesting as lesions arising at sites of intravenous catheter placement, venous sticks, skin biopsies, and other routine procedures that result in piercing of the dermis, as in this patient. The finding of pathergy should halt any further débridement or surgery, since these procedures would extend the process and would most likely result in an ongoing cycle of expansion and further débridement that could have catastrophic consequences.

Pyoderma Gangrenosum

Pyoderma gangrenosum is a neutrophilic dermatosis that presents as a rapidly advancing painful ulcer, most often on the legs, with an irregular, violaceous or gunmetal gray, undermined border.1 An atypical form appears on the hands, arms, or face, with deep erosions or superficial ulcerations that have a violaceous or blue-gray, bullous or granulomatous-appearing border. This form has also been referred to as neutrophilic dermatoses of the hands, and the patient's clinical presentation is consistent with this variant. Up to 70% of cases of pyoderma gangrenosum are associated with an underlying condition, such as inflammatory bowel disease, rheumatoid arthritis, and hematologic diseases (e.g., acute myeloid leukemia or myelodysplastic syndromes, hairy-cell leukemia, or monoclonal gammopathy).1 This patient reported a recent history of diarrhea and weight loss, which raises the possibility of an underlying inflammatory bowel disease, although presentation at his age would be unusual. Chronic, atypical cases of pyoderma gangrenosum, like the one in this patient, are often associated with acute myeloid leukemia, myelodysplastic syndromes, and IgA monoclonal gammopathies.1 This patient has thrombocytopenia and anemia, raising concern for a primary bone marrow disorder. Another noteworthy clinical finding in this patient is his prompt response, at least initially, to systemic glucocorticoids. Criteria for the diagnosis of pyoderma gangrenosum have been proposed.1,2 Major criteria are rapid progression of a painful, necrolytic, cutaneous ulcer that has an irregular, violaceous, and undermined border and the ruling out of other causes of cutaneous ulceration. Minor criteria are a history that is suggestive of pathergy, the presence of a systemic disease associated with pyoderma gangrenosum, the histopathological finding of dermal neutrophilia, and a rapid response to systemic glucocorticoid treatment. This patient meets both major criteria and three of the four minor criteria for this diagnosis.

Sweet's Syndrome

The diagnosis of acute febrile neutrophilic dermatosis (Sweet's syndrome) requires two major criteria (the abrupt occurrence of edematous erythematous-to-violaceous cutaneous lesions and a biopsy specimen that shows superficial edema and a deep, dense neutrophilic infiltrate without vasculitis) and at least two minor criteria (an associated underlying condition or exposure, fever, leukocytosis, and a rapid response to systemic glucocorticoid use). Like pyoderma gangrenosum, Sweet's syndrome is characterized by pathergy, as seen in this case. Also, 15% of adult cases of Sweet's syndrome are associated with hematologic neoplasms. The syndrome is also seen in patients who have solid-organ cancers, upper respiratory or gastrointestinal infections, human immunodeficiency virus infection, or inflammatory bowel disease; who have received vaccinations or other drugs (e.g., granulocyte colony-stimulating factor and all-trans retinoic acid); who have undergone bowel-bypass surgery; or who are pregnant. Sweet's syndrome typically does not induce the deep, progressive ulceration that was seen in this patient; however, localized Sweet's syndrome of the hands and atypical pyoderma gangrenosum (neutrophilic dermatoses of the hands) are sometimes considered to be the same entity.3 The patient did not have fever or leukocytosis, although he did have a response to glucocorticoids.

Summary

In this patient who had violaceous, bullous, and necrotic ulcers of the hands and arms; pathergy; a biopsy specimen that revealed a dense neutrophilic infiltrate; and an absence of systemic symptoms, my diagnosis is atypical chronic pyoderma gangrenosum, probably in association with a hematologic neoplasm. I would proceed with a re-review of his biopsy specimens by the dermatopathology service and, if inconclusive, with a repeat biopsy. I would recommend further evaluation for disorders associated with pyoderma gangrenosum, including consultations from the hematology and gastroenterology services.

Dr. Daniela Kroshinsky's Diagnosis

Atypical chronic pyoderma gangrenosum in association with a hematologic neoplasm.

Pathological Discussion

Dr. Mai P. Hoang: Histologic sections of the skin biopsy specimen taken at the first hospital revealed a dense infiltrate of neutrophils in the dermis. The overlying epidermis shows acanthosis, and there is papillary dermal edema (Figure 2A and 2BFigure 2Skin-Biopsy Specimen (Hematoxylin and Eosin).). Microbiologic cultures and special staining for microorganisms were negative. These findings are consistent with a diagnosis of pyoderma gangrenosum. The following four distinctive clinical and histologic variants of pyoderma gangrenosum have been described: ulcerative, pustular, bullous, and vegetative.4 Lesions characterized by ulceration are often associated with a systemic disease, including arthritis, inflammatory bowel disease, and monoclonal gammopathy. Pustular lesions are characterized by subcorneal pustules, papillary dermal edema, a dense neutrophilic infiltrate, and an association with inflammatory bowel disease. The bullous lesions have subepidermal vesiculation and a dense dermal neutrophilic infiltrate and are associated with hematologic neoplasms. The vegetative lesions (or superficial granulomatous pyoderma) are characterized by pseudoepitheliomatous hyperplasia, dermal abscess, and palisading granulomatous reaction and are typically not associated with systemic disease.4 This case would fit best with the bullous variant, and thus a hematologic neoplasm should be suspected. Dr. Robert P. Hasserjian: Bone marrow biopsy and aspiration were performed on the fourth hospital day. The biopsy specimen was normocellular for the patient's age and showed maturing myeloid and erythroid elements. Many megakaryocytes appeared dysplastic and small and had hypolobated nuclei and simplified nuclear contours (Figure 3AFigure 3Biopsy Specimen of the Bone Marrow and Peripheral-Blood Smear.). The aspirate smear revealed frequent dysplastic myeloid cells, including many forms with hypogranulated cytoplasm and bilobed nuclei (pseudo-Pelger–Huët cells). Erythroid maturation was normal, and the percentage of myeloblasts (3%) was not increased. An iron stain of the bone marrow aspirate showed the presence of abundant storage iron and no ring sideroblasts. The peripheral-blood smear showed circulating immature myeloid elements (myelocytes and metamyelocytes) and pseudo-Pelger–Huët cells (Figure 3B); circulating blasts were not seen. These morphologic findings were thought to be highly suspicious for a myelodysplastic syndrome; this diagnosis was confirmed by bone marrow cytogenetic analysis, which revealed an abnormal, complex karyotype, including deletion of the long arm of chromosome 5 (Figure 3C). On the basis of the presence of two morphologically dysplastic lineages (myeloid and megakaryocytic), the percentage of blasts in the bone marrow (<5%), and the percentage of blasts in the blood (<1%), this myelodysplastic syndrome was classified as refractory cytopenia with multilineage dysplasia, according to the 2008 World Health Organization classification.5 The presence of a complex karyotype is an adverse prognostic feature. The International Prognostic Scoring System (IPSS) for patients with myelodysplastic syndrome incorporates the percentage of blasts in the bone marrow, the number and degree of cytopenias, and the cytogenetic findings into a risk-group designation (low-risk, intermediate-1 risk, intermediate-2 risk, or high-risk). This patient's disease would fall in the intermediate-2 group; patients in this group have a median survival of approximately 1 year.6 Dr. Hoang: A variety of cutaneous manifestations have been reported in association with malignant tumors, including pyoderma gangrenosum, Sweet's syndrome, dermatomyositis, and necrobiotic xanthogranuloma. The two neutrophilic dermatoses — pyoderma gangrenosum and Sweet's syndrome — are seen most often in association with myeloid neoplasms, including myelodysplastic syndromes (as in this case), myeloproliferative neoplasms, and acute leukemias. Dermatomyositis, characterized by necrotic keratinocytes at the dermal–epidermal junction and marked dermal mucin deposition, is associated with lymphomas and ovarian carcinomas. Necrobiotic xanthogranuloma, characterized by granulomatous inflammation, cholesterol clefts, and striking multinucleated giant cells, is associated with paraproteinemia.

Discussion of Management

Dr. Kroshinsky: The diagnosis of atypical pyoderma gangrenosum had been made at the second hospital, and prednisone and cyclosporine had been prescribed, with a clinical response. Treatment of pyoderma gangrenosum involves wound care, including avoidance of trauma and débridement; treatment of any underlying condition; and immunosuppressive therapy.1 Although treatment of inflammatory bowel disease may induce remission of skin lesions in some patients, systemic immunosuppression is often required. The available agents, including glucocorticoids, dapsone, sulfapyridine, azathioprine, methotrexate, cyclophosphamide, cyclosporine, mycophenolate mofetil, tacrolimus, and tumor necrosis factor α (TNF-α) inhibitors, vary in their speed of onset of action, their side-effect profile, and their cost.1 In consultation with the clinical team, and because prednisone and cyclosporine had been effective before the attempt to taper them, we initially continued prednisone at 40 mg per day and increased the cyclosporine to 300 mg per day. Because the lesions showed no response, we added mycophenolate mofetil and tacrolimus topical gel. The lesions continued to progress, and new lesions appeared on the face and upper arms. On the eighth day, the patient began treatment with infliximab (a chimeric monoclonal antibody against TNF-α that blocks TNF-α action and induces apoptosis of T cells that express TNF-α), which has a rapid onset of action and has been reported to be helpful in cases of atypical pyoderma gangrenosum occurring on the hands and arms.7-9 Infliximab is preferred over other TNF-α blockers because of its rapid onset of action. The patient had a dramatic response, with improvement in all his lesions (Figure 1C). However, his overall clinical status deteriorated, with renal failure, volume overload, and pulmonary edema. Because the underlying hematologic disorder conferred a poor prognosis, the patient and his wife elected not to pursue aggressive treatment; in consultation with the palliative care service, care was transitioned to comfort measures only, and the patient died on the 29th hospital day. Dr. Eric S. Rosenberg (Pathology): Are there any questions or comments? A Physician: I have heard “team” mentioned during this conference. Would you describe how the team functions? Dr. Kroshinsky: At our hospital, the dermatology consult team consists of a full-time dermatologist who is assigned to the consult service with a resident. On behalf of this patient, the dermatology consult team dealt extensively with the team of caregivers, including the primary physicians and nurses and the consultants who helped interpret the test results that led to the diagnosis and the care plan.

Anatomical Diagnosis

Pyoderma gangrenosum due to a myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia).
This case was presented at the postgraduate course Dermatopathology Update, sponsored by the Harvard Medical School Department of Continuing Education and Department of Pathology, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Brigham and Women's Hospital. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the Departments of Dermatology (D.K.) and Pathology (M.P.H., R.P.H.), Massachusetts General Hospital; and the Departments of Dermatology (D.K.) and Pathology (M.P.H., R.P.H.), Harvard Medical School — both in Boston.
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sexta-feira, 13 de janeiro de 2012

Tuberculose super super ( totalmente) resistente



Nature | News

Totally drug-resistant TB emerges in India

Discovery of a deadly form of TB highlights crisis of 'mismanagement'.


Physicians in India have identified a form of incurable tuberculosis there, raising further concerns over increasing drug resistance to the disease1. Although reports call this latest form a “new entity”, researchers suggest that it is instead another development in a long-standing problem.
The discovery makes India the third country in which a completely drug-resistant form of the disease has emerged, following cases documented in Italy in 20072 and Iran in 20093.


An untreatable form of tuberculosis has been found in India.
Atul Loke/Panos
However, data on the disease, dubbed totally drug-resistant tuberculosis (TDR-TB), are sparse, and official accounts may not provide an adequate indication of its prevalence. Giovanni Migliori, director of the World Health Organization (WHO) Collaborating Centre for Tuberculosis and Lung Diseases in Tradate, Italy, suggests that TDR-TB is a deadlier iteration of the highly resistant forms of TB that have been increasingly reported over the past decade. “Totally resistant TB is not new at all,” he says.
Since the 1960s, two drugs — isoniazid and rifampicin — have been the standard TB treatment. Although episodes of resistance cropped up periodically, during the 1990s the incidence of multiple drug resistance grew significantly, leading researchers in 2006 to refer to it as extensively drug-resistant tuberculosis (XDR-TB). Surveillance data from the WHO indicate that XDR-TB is present in at least in 58 countries, with an estimated 25,000 cases occurring each year.
Epidemiologist Carole Mitnick of Harvard Medical School in Boston, Massachusetts, agrees that TDR-TB is not new, and points to the history of XDR-TB. “When XDR-TB was first named, it was a phenomenon that had existed but hadn’t gotten much attention before. TB in general doesn’t receive a lot of attention,” she says.

Inadequate care

Part of the increase in drug resistance is related to complications that arise in treating patients who are also infected with HIV — 13% of TB cases, according to the WHO. However, the greatest part of the problem results from the management of the disease.
Although the WHO describes TB as a “disease of poverty”, drug-resistant varieties might best be understood as resulting from poor treatment. According to a 2011 WHO report, fewer than 5% of newly diagnosed or previously treated patients are tested for drug resistance. And it is estimated that just 16% of patients with drug-resistant TB are receiving appropriate treatment.
“The cases are a story of mismanagement,” says Migliori. “Resistance is man-made, caused by exposure to the wrong treatment, the wrong regimen, the wrong treatment duration.”
In the management of TB, many factors affect whether the disease is cured or becomes resistant to treatment. Drug misuse or mismanagement can result if a patient does not follow a full course of treatment, or if the correct drugs are not available or patients with undiagnosed resistant TB receive inappropriate therapies.
Part of the problem also relates to TB testing. The WHO recommends sputum smear microscopy, a test developed more than one hundred years ago, as the standard diagnosis. Although inexpensive, this method is prone to false negatives, does not provide information on drug susceptibility, and test results can take several weeks — a large window of time for a patient to potentially receive the wrong drugs or transmit the infection. However in 2010, the WHO approved a new rapid and fully automated test, known as Xpert, which assesses resistance to the first-line drug rifampicin. As of July 2011, 26 countries are using Xpert and 145 are eligible to purchase kits at a reduced price.

Drug dearth

The fact that no new first-line TB drugs have been developed for half a century has probably contributed to the emergence of strains that are unresponsive to treatment, says Mitnick. “If you keep using the same drugs for that long, resistance is inevitable.”
Tuberculosis trails behind only HIV as the world’s leading cause of death from infectious disease. But in spite of its impact on human health and economic growth, it has not ranked among the pharmaceutical industry's priorities.
“The pharmaceutical industry had scant interest in TB for decades,” says Richard Chaisson, director of the Center for TB Research at the Johns Hopkins School of Public Health in Baltimore, Maryland. “The industry pretty much concluded it wasn’t an attractive market, there was not enough potential profit.”
But with a growing number of public–private partnerships in research, Chaisson says, industry interest is “an order of magnitude greater than it was a decade ago”.
As of 2011, there were 10 new or repurposed TB drugs in clinical trials that have the potential to either shorten treatment duration or improve therapy for resistant TB. Late-stage studies include a phase III trial by Bayer to assess whether its antibiotic moxifloxacin can help to reduce the duration of standard therapy from 6 months to 2. And both Tibotec and Novartis are in phase II trials for products that may be useful in treating drug-resistant forms.
Nature
doi:10.1038/nature.2012.9797

References

  1. Udwadia, Z. F., Amala, R. A., Ajbani, K. K. & Rodrigues, C. Clin. Infect. Dis. http://dx.doi.org/10.1093/cid/cir889 (2011).
    Show context
  2. Migliori, G. B., De Iaco, G., Besozzi, G., Centis, R. & Cirillo, D. M. Eurosurveillance 12, 3194 (2007).
    Show context
  3. Velayati, A. A. et al. Chest 136, 136420 (2009).
    Show context

Particula que pode resfriar a Terra


Researchers discover particle which could 'cool the planet' Friday, January 13, 2012 Earth Credit: NASA In a breakthrough paper published in Science, researchers from The University of Manchester, The University of Bristol and Sandia National Laboratories report the potentially revolutionary effects of Criegee biradicals. These invisible chemical intermediates are powerful oxidisers of pollutants such as nitrogen dioxide and sulfur dioxide, produced by combustion, and can naturally clean up the atmosphere. Although these chemical intermediates were hypothesised in the 1950s, it is only now that they have been detected. Scientists now believe that, with further research, these species could play a major role in off-setting climate change. The detection of the Criegee biradical and measurement of how fast it reacts was made possible by a unique apparatus, designed by Sandia researchers, that uses light from a third-generation synchrotron facility, at the Lawrence Berkeley National Laboratory's Advanced Light Source. The intense, tunable light from the synchrotron allowed researchers to discern the formation and removal of different isomeric species – molecules that contain the same atoms but arranged in different combinations. The researchers found that the Criegee biradicals react more rapidly than first thought and will accelerate the formation of sulphate and nitrate in the atmosphere. These compounds will lead to aerosol formation and ultimately to cloud formation with the potential to cool the planet. The formation of Criegee biradicals was first postulated by Rudolf Criegee in the 1950s. However, despite their importance, it has not been possible to directly study these important species in the laboratory. In the last 100 years, Earth's average surface temperature increased by about 0.8 °C with about two thirds of the increase occurring over just the last three decades. Most countries have agreed that drastic cuts in greenhouse gas emissions are required, and that future global warming should be limited to below 2.0 °C (3.6 °F). Dr Carl Percival, Reader in Atmospheric Chemistry at The University of Manchester and one of the authors of the paper, believes there could be significant research possibilities arising from the discovery of the Criegee biradicals. He said: "Criegee radicals have been impossible to measure until this work carried out at the Advanced Light Source. We have been able to quantify how fast Criegee radicals react for the first time. "Our results will have a significant impact on our understanding of the oxidising capacity of the atmosphere and have wide ranging implications for pollution and climate change. "The main source of these Criegee biradicals does not depend on sunlight and so these processes take place throughout the day and night." Professor Dudley Shallcross, Professor in Atmospheric Chemistry at The University of Bristol, added: "A significant ingredient required for the production of these Criegee biradicals comes from chemicals released quite naturally by plants, so natural ecosystems could be playing a significant role in off-setting warming.'

quarta-feira, 11 de janeiro de 2012

A melhor ciência na midia social


http://shortyawards.com/category/science/2



Sequenciamento de genoma por U&1000

Do Blog Digital Pathology


NEW YORK (Reuters) - After years of predictions that the "$1,000 genome" - a read-out of a person's complete genetic information for about the cost of a dental crown - was just around the corner, a U.S. company is announcing Tuesday that it has achieved that milestone and taken the technology several steps ahead. The new genome-sequencing machine from Ion Torrent, a division of Life Technologies Corp., in Guilford, Connecticut, is 1,000 times more powerful than existing technology, says CEO and chairman Jonathan Rothberg. Taking up about as much space as an office printer, it can sequence an entire genome in a single day rather than six to eight weeks required only a few years ago. The new sequencer, says cardiologist Eric Topol, chief academic officer of private California hospital and doctor network Scripps Health, "represents an exceptional advance and can change medicine." Ion Torrent will sell the tabletop machine, called the Ion Proton Sequencer, for $99,000 to $149,000, making it affordable for large medical practices or clinics; existing sequencers cost up to $750,000. The computer chip and biochemicals to sequence a genome will cost $1,000, compared to, for example, $3,000 to test for mutations just in the BRCA genes that raise the risk of breast and ovarian cancer and $5,000 for a complete genome sequencing by Ion Torrent competitor Illumina Inc. For a graphic on the shrinking cost of genome sequencing, see: http://link.reuters.com/xys85s For now, Rothberg expects research labs to be his main customers, using Proton to obtain the complete genome sequence of people with cancer or autism, for instance, and thereby elucidate a disease's underlying genetic causes as well as possible ways to treat it. The company has signed on Baylor College of Medicine, Yale School of Medicine and the Broad Institute as its first customers. Other scientists and physicians, however, say the long-awaited arrival of the $1,000 genome opens the door to widespread whole-genome sequencing even of people who are not ill. And that raises ethical, legal, and medical issues that experts are only beginning to grapple with. "I'm a big proponent of bringing genetics into the clinic," says Thomas Quertermous, chief of the division of cardiovascular medicine at Stanford University and an expert in the genetics of heart disease. "But it has to be done in a timely way, and not before its time." Babies might be first in line for whole-genome sequencing. Every state requires newborns to be screened for at least 29 genetic diseases. "If the cost of whole-genome sequencing gets sufficiently low, you could sequence all the genes in a newborn" for less than the individual tests and follow-ups required when one comes back positive, says Richard Lifton, chairman of the genetics department at Yale University. "I'm increasingly confident that's going to happen. But we need to be careful how we utilize this information. Do you tell a newborn's parents his apoE status" -- that is, whether he has the form of a gene that raises the risk of Alzheimer's disease? The cost of whole-genome sequencing will continue to plummet. Lifton foresees a "zero-dollar genome," making it likely that "we will just do it as part of routine clinical care" for children and adults. A Yale team led by Murat Gunel has already used partial genome sequencing of the 1.5 percent of the genome, called the exome, that codes for proteins to determine the cause of a mysterious and still unnamed genetic disease that results in severe brain malformations. Because no genes had been identified as causing the malformation, it was not possible to do a standard genetic test, which reveals whether a particular gene is normal or mutated. But exome sequencing showed that a previously unknown gene on chromosome 19 is responsible, he and colleagues reported in 2010. "The new Proton instrument is a big step up," says Lifton. "It promises to markedly increase the speed and reduce the cost of genome-level sequencing." TSUNAMI OF DATA The discovery of the mutation behind the mysterious genetic disorder demonstrated the advantage of whole-genome sequencing compared to single-gene tests, as scientists can't test for a gene they don't know exists. Beyond such uses, say experts, whole-genome sequencing might not be the medical miracle that proponents forecast. One problem is that the costs only start with the actual sequencing. "The cost of understanding the sequence will be much, much higher," says bioethicist Hank Greely of Stanford University. He participated in a 2010 project that sequenced the full genome of Stanford bioengineer Stephen Quake. The sequencing cost $48,000. But because it found 2.6 million DNA misspellings and 752 other genetic glitches, says Greely, "it took a few hundred thousand dollars worth of labor from Ph.D. students and faculty working 4,000 to 5,000 hours to understand what the sequence meant" -- that Quake had a higher-than-average risk of sudden cardiac death, a lower risk of Alzheimer's, and a higher risk of prostate cancer. Another challenge is that whole-genome sequencing generates a tsunami of data. It would take a genetic counselor some five hours to explain what a typical genome means, further adding to the true cost. The United States has about 2,500 genetic counselors, not nearly enough to meet the need if whole-genome sequencing becomes widespread. Might doctors take up the slack? "Surveys show that 90 percent of patients trust their physician to explain genomics data to them," says Scripps' Topol. "And 90 percent of physicians say they don't feel comfortable with genomics data." Although many bioethicists focus on the psychological harm patients might suffer when DNA tests show an elevated risk of cancer, diabetes, Parkinson's, and other diseases, genomics information could also threaten patients' physical health if it is misconstrued. A woman whose DNA sequencing shows she does not carry BRCA mutations that raise her risk of breast cancer "might say, great, I don't need mammograms," says Stanford's Greely. "But a negative BRCA test reduces her risk of breast cancer from 12 percent to 11.96 percent. My dread is less that patients will be damaged psychologically and more that they will misunderstand (genome sequence data) and do stupid things." Unlike tests that detect glitches in genes that a patient or physician asks to have checked (those that raise the risk of, say, colon cancer if that disease runs in the family), and unlike the dozens of genes that "personal genetics" companies test for, whole-genome sequencing reveals every bit of information the genome contains about diseases or traits. Given the ubiquity of mutations, everyone carries genes that predispose them to more than one serious or lethal disease. Bioethicists are only beginning to study how that knowledge might affect someone's decisions, from marrying or having children to saving for retirement. Another challenge is that although a person's genome doesn't change, its meaning will. As scientists uncover more DNA variants that protect against disease and variants that make it more likely, a genome sequence that meant one thing in 2012 will have a different meaning in 2013, not to mention 2020. A DNA variant that was once thought to be dangerous "might turn out to be benign if countered by another," says Greely. "Whose responsibility will it be to tell you that, years later?" Today's DNA testing companies offer subscriptions that give customers regular updates like that. Geneticists are also still struggling with the fact that most of the risk genes raise the likelihood that the person will develop the disease only slightly. "The bottom line is, the effect size is so small it's virtually insignificant clinically," says Quertermous. "So how should doctors incorporate that knowledge into their armamentarium? They won't be able to look at 6 billion data bits" - the amount in a whole-genome scan - "and evaluate what it means for patients." Knowing a patient's whole-genome sequence, even if it raises the risk of diseases by only a few percent, might lead malpractice-wary doctors to order follow-up tests. If someone's genome suggests an elevated risk of heart disease, for instance, a physician might feel compelled to order regular cardiac CT angiograms, which cost $1,500 or more. That would not only raise health-care costs, but might put patients through a physically and psychologically onerous ordeal unnecessarily. "There is no evidence that 'positive' (DNA) tests, based only on the screening for common genetic variations, will justify a specific medical follow-up and procure a medical benefit to individuals," argues geneticist Thierry Frebourg of University Hospital in Rouen, France in a commentary in an upcoming issue of the European Journal of Human Genetics. Instead, whole-genome sequencing might join the ranks of diagnostics, such as PSA tests for prostate cancer, that cost tens of millions of dollars a year but do not benefit patients, let alone save lives. INEFFECTIVE DRUGS Full-genome sequencing could provide real benefits in determining which patients will benefit from a drug. For instance, only half the hepatitis C patients who take Pegasys, a $50,000-a-year drug from Roche Holding AG's Genentech, and half the rheumatoid arthritis patients who take $26,000-a-year Enbrel from Amgen Inc and Pfizer Inc, benefit from them, notes Scripps' Topol, who analyzes the potential benefits of genomic medicine in his upcoming book, The Creative Destruction of Medicine. Using genomic data to identify which patients will and will not benefit could save patients and insurers tens of billions of dollars a year now spent on ineffective drugs. If genetic information causes patients to take better care of themselves - eating more healthfully if they carry genes that raise the risk of diabetes or heart disease, for instance - they can improve health. One 2010 study found that of people who bought direct-to-consumer genetic testing by companies such as 23andme, 34 percent said the results made them more careful about their diet and 14 percent exercised more. Others incorrectly see DNA as destiny, and interpret an increased genetic risk of, say, obesity as a license to overeat, thinking they are fated to be fat. "Good" genes might lead to equally dangerous behavior. "A patient with hypertension might be told by his doctor, 'I've looked at your DNA and you're clean!'," says Stanford's Quertermous. "He might think, great, I don't need to check my blood pressure anymore or even take my medication." As the science advances, however, the value of whole-genome sequencing to patients will grow. The common DNA variants that have been identified "account for only a small part of the heritability of disease," says Kari Stefansson, founder, chairman, and CEO of deCode Genetics of Reykjavik, Iceland. "The expectation is that a significant part of the missing heritability lies in rare variants, and to find those you have to do whole-genome sequencing." deCode is sequencing the complete genomes of 3,750 Icelanders, and has so far identified rare variants with large effects on the risk of ovarian cancer, glioma, gout, and heart conditions that require a pacemaker. Those discoveries would have been difficult or impossible without whole-genome sequencing. Whole-genome sequencing also promises to address one of the most troubling problems with current DNA tests, which probe some of the 1,500 or so genes that have been associated with disease out of a total of 22,000 human genes. But scientists do not know how disease risk is raised or lowered by "moderator genes," which affect other genes. "Do we know how combinations of genes affect risk?" Stanford's Quertermous asks. "The answer is completely no." As a result, the disease risk that is calculated from current genetic tests might be inaccurate. With millions of whole-genome sequences, biologists believe, they can begin to work out those crucial combined effects. One upcoming study shows how important gene combinations can be. In research scheduled for publication in the journal Human Molecular Genetics, scientists led by Charis Eng of the Cleveland Clinic examined the incidence of breast, thyroid, and other cancers in patients carrying a mutation in a gene called PTEN. Such mutations are typically interpreted as raising the risk of cancer. But Eng found that the presence or absence of mutations in another gene, called SDHx, can alter that risk. "Current genetic testing, which looks at only a few genes, is like trying to forecast the stock market by looking at just 26 stocks," says Eng of the Cleveland Clinic. Such limited genetic data can be misleading. In a separate study of 44 patients, scheduled for publication in the European Journal of Human Genetics, Eng and colleagues find that family medical history assessed the risk of breast, colon and prostate cancer more accurately than DNA sequencing. For instance, family history correctly classified eight women as being at high risk for breast cancer. But only one of the eight was so classified by DNA. "For now, family health history is a better predictor of cancer risk than genomic testing, which looks at too few genes," Eng says. Because whole-genome sequencing is not yet being marketed to consumers, the U.S. Food and Drug Administration has not taken a position on it. But it is concerned by existing tests that are sold directly to the public by Navigenics, Pathway Genomics and 23andme, and has invited companies that sell them to meet with agency officials to work out ways "to provide consumers with accurate, reliable kits," says FDA spokeswoman Erica Jefferson. Until then, the companies are prohibited from marketing the tests to the public. "Manufacturers have not provided scientific evidence about the accuracy and reliability of their tests, which can lead to incorrect treatment decisions with serious health consequences," says Jefferson. "The risk of getting a disease depends on a set of complex interactions," so "even people with the same genetic make-up may have different risks of disease." Gene-sequencing companies understand the challenges. "Each genome has probably 24,000 mutations that we can understand," says Ion Torrent's Rothberg. "But there are probably 400 that have never been seen before" and whose significance for health is an enigma. Ion Torrent is working on algorithms to determine the medical significance of the millions of DNA glitches that will be found in every genome. Companies such as Personalis, of Palo Alto, California, have sprung up to determine the medical significance of whole-genome sequences. That will take years. "We recognize this is just the beginning," Rothberg says. (Editing by Michele Gershberg and Cynthia Osterman)

terça-feira, 10 de janeiro de 2012

Twitter pode ajudar a detectar epidemias?

Twitter Revealed Epidemic Two Weeks Before Health Officials


01/10/12 by Kate Freeman Health providers have suspected for some time that social media might be an early indicator of an epidemic. Now they have proof. In particular, a new report shows that Twitter provided an early account of the 2010 cholera outbreak in Haiti. According to the study published in the American Journal of Tropical Medicine and Hygiene, Internet news and social media were faster transmitters of information in tracking the cholera epidemic in Haiti than health officials. The tweets provided information that health officials wouldn’t report until two weeks later. “We can definitely use these sources to get early information about how a disease is spreading, and consequently help inform control or response efforts sooner,” says the report’s lead author, Rumi Chunara, Ph.D. Chunara and the other two authors of the study, Dr. Jason R. Andrews, MD, and John S. Brownstein, Ph.D., determined sites like Twitter can help doctors and epidemiologists pinpoint the speed at which epidemics grow. “One of the great benefits of these novel data streams is that they are available in real time,” Chunara says. The next step, she said, would be determining how to utilize real-time data concurrently, or even prospectively, to control outbreaks. SEE ALSO: How Twitter Tracks the Spread of Disease in Real Time To conduct the study, the researchers created a timeline by searching for the term cholera and the #cholera hashtag on Twitter from Oct. 20 to Nov. 3, 2010. In the two weeks before health officials reported the outbreak, 65,728 tweets with the word “cholera” were posted on Twitter. The authors also used free information from HealthMap, a website that monitors news of outbreaks around the world. From HealthMap, they compiled 188,819 tweets in the first 100 days after the initial upsurge. “Of course any data type will have its own biases and noise, and that is one of the main challenges in working with social media,” Chunara says. Examining social media could also help health officials tackle up-to-the-moments needs of the infected public and keep disease from spreading. Since the epidemic, 520,000 Haitians have been infected with Cholera and nearly 7,000 have died from the infection. Cholera is an acute intestinal infection caused by tainted water and food supplies. Of course, there’s a downside to social media reporting of epidemics as well. Tweets about swine flu in 2009 created a panic on Twitter while actual cases were at the lowest number. As real-life outbreaks increased, talk about swine flu on Twitter decreased. Still, Twitter provided researchers additional real-time data to track the disease and the public’s reaction.