Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease

Nature Medicine 14, 504 (2008). doi:10.1038/nm1747

Authors: Jeffrey H Kordower, Yaping Chu, Robert A Hauser, Thomas B Freeman & C Warren Olanow

Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.

Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation

Nature Medicine 14, 501 (2008). doi:10.1038/nm1746

Authors: Jia-Yi Li, Elisabet Englund, Janice L Holton, Denis Soulet, Peter Hagell, Andrew J Lees, Tammaryn Lashley, Niall P Quinn, Stig Rehncrona, Anders Björklund, Håkan Widner, Tamas Revesz, Olle Lindvall & Patrik Brundin

Two subjects with Parkinson's disease who had long-term survival of transplanted fetal mesencephalic dopaminergic neurons (11–16 years) developed α-synuclein–positive Lewy bodies in grafted neurons. Our observation has key implications for understanding Parkinson's pathogenesis by providing the first evidence, to our knowledge, that the disease can propagate from host to graft cells. However, available data suggest that the majority of grafted cells are functionally unimpaired after a decade, and recipients can still experience long-term symptomatic relief.

Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years

Nature Medicine 14, 507 (2008). doi:10.1038/nm1752

Authors: Ivar Mendez, Angel Viñuela, Arnar Astradsson, Karim Mukhida, Penelope Hallett, Harold Robertson, Travis Tierney, Renn Holness, Alain Dagher, John Q Trojanowski & Ole Isacson

Postmortem analysis of five subjects with Parkinson's disease 9–14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies.

Replacing PCR with COLD-PCR enriches variant DNA sequences and redefines the sensitivity of genetic testing

Nature Medicine 14, 579 (2008). doi:10.1038/nm1708

Authors: Jin Li, Lilin Wang, Harvey Mamon, Matthew H Kulke, Ross Berbeco & G Mike Makrigiorgos

PCR is widely employed as the initial DNA amplification step for genetic testing. However, a key limitation of PCR-based methods is the inability to selectively amplify low levels of mutations in a wild-type background. As a result, downstream assays are limited in their ability to identify subtle genetic changes that can have a profound impact in clinical decision-making and outcome. Here we describe co-amplification at lower denaturation temperature PCR (COLD-PCR), a novel form of PCR that amplifies minority alleles selectively from mixtures of wild-type and mutation-containing sequences irrespective of the mutation type or position on the sequence. We replaced regular PCR with COLD-PCR before sequencing or genotyping assays to improve mutation detection sensitivity by up to 100-fold and identified new mutations in the genes encoding p53, KRAS and epidermal growth factor in heterogeneous cancer samples that had been missed by the currently used methods. For clinically relevant microdeletions, COLD-PCR enabled exclusive amplification and isolation of the mutants. COLD-PCR will transform the capabilities of PCR-based genetic testing, including applications in cancer, infectious diseases and prenatal identification of fetal alleles in maternal blood.

Noninvasive in vivo imaging of pancreatic islet cell biology

Nature Medicine 14, 574 (2008). doi:10.1038/nm1701

Authors: Stephan Speier, Daniel Nyqvist, Over Cabrera, Jia Yu, R Damaris Molano, Antonello Pileggi, Tilo Moede, Martin Köhler, Johannes Wilbertz, Barbara Leibiger, Camillo Ricordi, Ingo B Leibiger, Alejandro Caicedo & Per-Olof Berggren

Advanced imaging techniques have become a valuable tool in the study of complex biological processes at the cellular level in biomedical research. Here, we introduce a new technical platform for noninvasive in vivo fluorescence imaging of pancreatic islets using the anterior chamber of the eye as a natural body window. Islets transplanted into the mouse eye engrafted on the iris, became vascularized, retained cellular composition, responded to stimulation and reverted diabetes. Laser-scanning microscopy allowed repetitive in vivo imaging of islet vascularization, beta cell function and death at cellular resolution. Our results thus establish the basis for noninvasive in vivo investigations of complex cellular processes, like beta cell stimulus-response coupling, which can be performed longitudinally under both physiological and pathological conditions.

Assessing fetal nerve cell grafts in Parkinson's disease

Nature Medicine 14, 483 (2008). doi:10.1038/nm0508-483

Authors: Heiko Braak & Kelly Del Tredici

Three postmortem studies examine long-term fetal transplants in subjects with advanced Parkinson's disease. The findings—such as the development of parkinsonian pathology in some transplanted neurons—underscore the limitations of this approach.

β-adrenergic signaling in heart failure—adapt or die

Nature Medicine 14, 485 (2008). doi:10.1038/nm0508-485

Author: Thomas Eschenhagen

About 25% of the African-American population carries a gene variant that seems to protect against heart failure. The findings may have implications for the use of β-blockers (pages 510–517).

Bedside to bench: Interfering with leukemic stem cells

Nature Medicine 14, 494 (2008). doi:10.1038/nm0508-494

Authors: Daniela S Krause & Richard A Van Etten

Kinase inhibitors such as imatinib (Gleevec) have improved the outlook for many people with chronic myeloid leukemia and related blood disorders. But such drugs do not target the leukemia stem cell population and may not be curative. Krause and Van Etten discuss several clinical studies that suggest that interferon-α may provide a solution by selectively eliminating leukemic stem cells—although only more basic research will tell us whether this is true and how it may happen.

A shot in the arm for mast cells

Nature Medicine 14, 489 (2008). doi:10.1038/nm0508-489

Authors: Bali Pulendran & Santa J Ono

The search is on for for vaccine adjuvants that boost the innate immune response and complement existing adjuvants. Mast cell activators may be one option (pages 536–541).

Bench to bedside: BRCA: From therapeutic target to therapeutic shield

Nature Medicine 14, 495 (2008). doi:10.1038/nm0508-495

Author: Neil P Shah

Three studies examine how resistance to chemotherapy develops in cancers deficient in BRCA1 and BRCA2. The mechanism involves restoration of BRCA1 and BRCA2 activity. Shah examines the implications for the clinic, such as the potential value of continuing treatment with cisplatin and similar agents even after drug resistance develops.

Dust mites' dirty dealings with dendritic cells

Nature Medicine 14, 487 (2008). doi:10.1038/nm0508-487

Author: Dean Sheppard

Allergens stimulate lymphocytes to become factories for secreted proteins that cause organ dysfunction in allergic diseases. Allergens are now shown to target dendritic cells, the cells responsible for processing and presenting antigens to T cells (pages 565–573).

Hungry for sleep

Nature Medicine 14, 477 (2008). doi:10.1038/nm0508-477

Author: Cassandra Willyard

For many years, epidemiologists have linked sleep deprivation to poor health. Now, even as the average amount of shuteye people get continues to diminish, new evidence from biological research helps explain how missing out on sleep might contribute to obesity and diabetes. Cassandra Willyard asks what happens when we ignore the sandman.

Getting embryonic stem cell therapy right

Nature Medicine 14, 467 (2008). doi:10.1038/nm0508-467

Embryonic stem cell therapy may soon enter clinical trials. The US Food and Drug Administration (FDA) will need to provide clear guidance on how it will regulate such trials and ensure that politics will not cloud the regulatory process.

Haunted house

Nature Medicine 14, 468 (2008). doi:10.1038/nm0508-468a

The use of ghostwriters to pen scientific papers is nothing new, but if we want to get rid of them, stricter authorship rules may not be sufficient for a successful exorcism.

Translational moves

Nature Medicine 14, 468 (2008). doi:10.1038/nm0508-468b

In this issue of the journal, we introduce some changes to underscore our long-standing interest in translational research.

Straight talk with... Maria Freire

Nature Medicine 14, 472 (2008). doi:10.1038/nm0508-472

Today, the practice of moving technologies from the lab to the marketplace is commonplace. But when Maria Freire began dabbling in the process a quarter-century ago, it had only just started receiving serious attention from the US government. As former head of the Office of Technology Transfer at the US National Institutes of Health (NIH), and more recently as chief executive officer and president of the Global Alliance for TB Drug Development (TB Alliance), Freire helped commercialize numerous new health technologies. This past March, she became president of the Albert and Mary Lasker Foundation, which each year awards the nation's most distinguished honors for science, often dubbed 'America's Nobels'. She spoke with Alisa Opar about her previous work advancing biomedical research and her new role at the foundation.