Groen A.K.,University of Groningen |
Nieuwdorp M.,University of Amsterdam |
Nieuwdorp M.,University of Gothenberg
Clinical Therapeutics | Year: 2015
Purpose The contribution of intestinal bacterial strains (gut microbiota) in human metabolism and obesity is being increasingly recognized. The goal of this article was to provide a commentary on the clinical usefulness of these data. Methods We performed a review of the currently available articles on PubMed. Findings Because most of the data are based on germ-free animal research, translation to human disease may be difficult. However, changes in the intestinal bacterial composition and subsequent altered diversity have been associated with the presence of chronic low-grade inflammation, a known feature of insulin resistance and type 2 diabetes mellitus. Implications It is still not proven whether intestinal bacteria play a causal role in glucose and lipid metabolism. Intervention studies including fecal transplantation and supplementation of single bacterial strains in humans might provide more insight. Moreover, prospective cohorts of healthy subjects using fecal samples collected at baseline can help to identify causally involved specific intestinal bacterial strains that drive aberrant human metabolism. Ultimately, it would be a great asset if potential diagnostic and therapeutic targets could be derived from this novel player in human cardiometabolism. © 2015 Elsevier HS Journals, Inc. All rights reserved.
Johansson H.,Gothenburg University |
Oden A.,Gothenburg University |
Kanis J.,University of Sheffield |
McCloskey E.,University of Sheffield |
And 8 more authors.
Osteoporosis International | Year: 2011
We studied the nature of the relationship between bone mineral density (BMD) and the risk of death among elderly men. BMD was associated with mortality risk and was independent of adjustments for other co-morbidities. A piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (=0.020). Low BMD was associated with a substantial excess risk of death, whilst a higher than average BMD had little impact on mortality. Introduction: Previous studies have demonstrated an association between low BMD and an increased risk of death among men and women. The aim of the present study was to examine the pattern of the risk in men and its relation to co-morbidities. Methods: We studied the nature of the relationship between BMD and death among 3,014 elderly men drawn from the population and recruited to the MrOS study in Sweden. Baseline data included general health questionnaires, life style questionnaires and BMD measured using DXA. Men were followed for up to 6.5 years (average 4.5 years). Poisson regression was used to investigate the relationship between BMD, co-morbidities and the hazard function of death. Results: During follow-up, 382 men died (all-cause mortality). Low BMD at all measured skeletal sites was associated with increased mortality. In multivariate analyses, the relationship between BMD and mortality was non-linear, and a piecewise linear function described the relationship more accurately than assuming the same gradient of risk over the whole range of BMD (=0.020). Conclusions: Low BMD is associated with a substantial excess risk of death compared to an average BMD, whereas a higher than average BMD has a more modest effect on mortality. These findings, if confirmed elsewhere, have implications for the constructing of probability-based fracture risk assessment tools. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation.
Piccinin A.M.,University of Victoria |
Muniz G.,MRC Biostatistics Unit |
Matthews F.E.,MRC Biostatistics Unit |
Johansson B.,University of Gothenberg
Journals of Gerontology - Series B Psychological Sciences and Social Sciences | Year: 2011
Objective. The terminal cognitive decline hypothesis has been debated for almost 50 years. This hypothesis implies a change in rate of decline within an individual. Therefore, we examine the hypothesis from a within-person perspective using a time to death chronological structure. Method. Scores on a Swedish version of the Wechsler Adult Intelligence Scale Information and Block Design scores from 461 OCTO-Twin Study participants with confirmed death dates were modeled using quadratic growth curve models including both age and distance from death at study entry, sex, education, and dementia diagnosis as covariates of initial performance and of linear and quadratic change over time. Results. Information scores showed statistically significant evidence of slight within-person acceleration of declines in the no dementia group. Individuals with incident dementia declined more quickly, and those who were closer to death at study baseline had a stronger acceleration. Block Design scores declined but did not show evidence of such acceleration either within or across individuals. Decline was faster in incident cases closer to death at study entry. Discussion. Within-person evidence of terminal decline is not as strong as previously published between-person results. Strategies for focusing models on longitudinal aspects of available data and the extent to which lack of within-person evidence for terminal decline may stem from common data limitations are discussed. © The Author 2011.
Hamsher A.E.,University of Pittsburgh |
Xu H.,University of Pittsburgh |
Guy Y.,University of Pittsburgh |
Sandberg M.,University of Gothenberg |
Weber S.G.,University of Pittsburgh
Analytical Chemistry | Year: 2010
Electroosmotic sampling is a potentially powerful method for pulling extracellular fluid into a fused-silica capillary in contact with the surface of tissue. An electric field is created in tissue by passing current through an electrolyte-filled capillary and then through the tissue. The resulting field acts on the counterions to the surface charges in the extracellular space to create electroosmotic fluid flow within the extracellular space of a tissue. Part of the development of this approach is to define conditions under which electroosmotic sampling minimizes damage to the tissue, in this case organotypic hippocampal slice cultures (OHSCs). We have assessed tissue damage by measuring fluorescence resulting from exposing sampled tissue to propidium iodide solution 16-24 h after sampling. Sampling has been carried out with a variety of capillary diameters, capillary tip-tissue distances, and applied voltages. Tissue damage is negligible when the power (current x potential drop) created in the tissue is less than 120 μW. In practical terms, smaller capillary i.d.s, lower voltages, and greater tissue to capillary distances lead to lower power. © 2010 American Chemical Society.
Woodcock A.,University of Manchester |
Bateman E.D.,University of Cape Town |
Busse W.W.,University of Wisconsin - Madison |
Lotvall J.,University of Gothenberg |
And 5 more authors.
Respiratory Research | Year: 2011
Background: Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma.Methods: Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV1) 50-80% of predicted normal value and FEV1reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV1at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV1.Results: A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV1compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV1at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV1than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups.Conclusions: FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma.Trial registration: NCT00398645. © 2011 Woodcock et al; licensee BioMed Central Ltd.
Shen M.,CAS Institute of Tibetan Plateau Research |
Shen M.,Chinese Academy of Sciences |
Piao S.,CAS Institute of Tibetan Plateau Research |
Piao S.,Chinese Academy of Sciences |
And 18 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
In the Arctic, climate warming enhances vegetation activity by extending the length of the growing season and intensifying maximum rates of productivity. In turn, increased vegetation productivity reduces albedo, which causes a positive feedback on temperature. Over the Tibetan Plateau (TP), regional vegetation greening has also been observed in response to recent warming. Here, we show that in contrast to arctic regions, increased growing season vegetation activity over the TP may have attenuated surface warming. This negative feedback on growing season vegetation temperature is attributed to enhanced evapotranspiration (ET). The extra energy available at the surface, which results from lower albedo, is efficiently dissipated by evaporative cooling. The net effect is a decrease in daily maximum temperature and the diurnal temperature range, which is supported by statistical analyses of in situ observations and by decomposition of the surface energy budget. A daytime cooling effect from increased vegetation activity is also modeled from a set of regional weather research and forecasting (WRF) mesoscale model simulations, but with a magnitude smaller than observed, likely because the WRF model simulates a weaker ET enhancement. Our results suggest that actions to restore native grasslands in degraded areas, roughly one-third of the plateau, will both facilitate a sustainable ecological development in this region and have local climate cobenefits. More accurate simulations of the biophysical coupling between the land surface and the atmosphere are needed to help understand regional climate change over the TP, and possible larger scale feedbacks between climate in the TP and the Asian monsoon system.
Bauer S.B.,Harvard University |
Nijman R.J.M.,University of Groningen |
Drzewiecki B.A.,Yeshiva University |
Sillen U.,University of Gothenberg |
Hoebeke P.,Ghent University
Neurourology and Urodynamics | Year: 2015
Aims The objective of this document created by the ICCS standardization subcommittee is to provide a uniform guideline on measurement, quality control and documentation of urodynamic studies in children. Methods This guideline was created using expert opinion and critical review of the published literature on urodynamic studies in children. Currently no standardized guideline or level 1 data exists on the proper technique for this subject matter. Results The document provides a throughout explanation on how to approach a child who presents with lower urinary tract dysfunction, whether it be of neurogenic, anatomic or functional origin. Formation of an urodynamic question after a comprehensive history and physical examination is paramount in selecting the urodynamic study(ies) that will be most appropriate for each child. Appropriate application of each test with careful consideration of the needs of the child and family will provide the most accurate and reproducible results. Recommendations on how to execute each of the components of an urodynamic study as well as interpretation are included in the document. Conclusions Urodynamic studies have become a major tool in evaluating lower urinary tract dysfunction in children. There are many subtleties in performing these studies in children in juxtaposition to adults; therefore, adaptations specific to children must be made to achieve accurate and reproducible results. Uniformity in how the studies are conducted from center to center will allow for healthier transparency and enhanced comparison of results in both clinical and research situations. © 2015 Wiley Periodicals, Inc.
PubMed | University of Gothenberg, University of Groningen, Ghent University, Harvard University and Yeshiva University
Type: Journal Article | Journal: Neurourology and urodynamics | Year: 2015
The objective of this document created by the ICCS standardization subcommittee is to provide a uniform guideline on measurement, quality control and documentation of urodynamic studies in children.This guideline was created using expert opinion and critical review of the published literature on urodynamic studies in children. Currently no standardized guideline or level 1 data exists on the proper technique for this subject matter.The document provides a throughout explanation on how to approach a child who presents with lower urinary tract dysfunction, whether it be of neurogenic, anatomic or functional origin. Formation of an urodynamic question after a comprehensive history and physical examination is paramount in selecting the urodynamic study(ies) that will be most appropriate for each child. Appropriate application of each test with careful consideration of the needs of the child and family will provide the most accurate and reproducible results. Recommendations on how to execute each of the components of an urodynamic study as well as interpretation are included in the document.Urodynamic studies have become a major tool in evaluating lower urinary tract dysfunction in children. There are many subtleties in performing these studies in children in juxtaposition to adults; therefore, adaptations specific to children must be made to achieve accurate and reproducible results. Uniformity in how the studies are conducted from center to center will allow for healthier transparency and enhanced comparison of results in both clinical and research situations.
News Article | February 23, 2017
Diabetes is a leading cause of kidney disease, a serious, often fatal complication that is difficult to diagnose in early, potentially treatable stages. Now, a research team at the Icahn School of Medicine at Mount Sinai has revealed biological pathways involved in diabetic kidney disease, providing hope that both early diagnostic tests and targeted treatment can be designed. The study, published in Diabetes, shows that oxidative stress in the "power plants" within a population of kidney cells progressively impairs the ability of the bean-shaped organs to strain blood for waste products and produce urine. The research team also found a cellular receptor that can be blocked to modulate that stress reaction. Blocking that receptor saved the kidneys in mice genetically destined to develop diabetic kidney failure. About 30 percent of patients with type 1 (juvenile onset) diabetes and 10 to 40 percent of those with type 2 (adult onset) diabetes eventually will suffer from kidney failure, according to the National Kidney Foundation. When that happens, patients must turn to dialysis or kidney transplantation, if available. "Diabetic kidney disease is one of the major causes of death in diabetic patients, and is also the leading single cause of end-stage renal disease in the United States," says the study's senior investigator, Ilse S. Daehn, PhD, Assistant Professor of Medicine (Nephrology) at the Icahn School of Medicine at Mount Sinai. "Our findings open new diagnostic opportunities for early detection and potential therapeutic strategies to protect against further renal damage in patients." The study's findings essentially offer a "fundamental paradigm shift in our understanding of the development and treatment of diabetic kidney disease," says Dr. Daehn, who is also a member of The Charles Bronfman Institute for Personalized Medicine. Investigators focused on the kidney's glomerulus -- globular bodies, full of capillaries and other structures, that serve as the first stage and the key unit in the filtration of blood for waste products to be expelled in urine. The research team studied three different cell types that interact within the glomerulus, using two sets of mice. One group naturally develops diabetic kidney disease and the other group is naturally resistant to the disorder. They discovered that in mice prone to kidney disease, endothelial cells were affected. In these wafer-like cells, which form the inner lining of blood vessels, the mitochondria -- cellular subunits that act like power plants, producing energy -- were stressed, and so made excess amounts of reactive oxygen species (ROS). These are molecules that have important roles in cell signaling but, when overproduced, can damage cell proteins and DNA. This process begins to destroy podocytes, cells that wrap around and work with capillaries and the other cell types in the glomerulus. The glomerulus eventually becomes brittle, the capillaries collapse, and kidneys become leaky, shedding essential body proteins. Progressive damage leads to kidney failure, resulting in end-stage kidney disease. The research team was able to measure, in susceptible mice, molecules linked to excess ROS, suggesting that a biomarker could be developed that signals early development of kidney disease in humans. And knowing that ROS excess leads to kidney disease implies that agents that collect ROS molecules within the kidney might provide a potential therapy, Dr. Daehn says. Investigators then looked for "upstream" regulators of mitochondrial stress within the endothelium in the glomerulus and discovered a pathway that helps manage this oxidative stress. This pathway produced excess quantities of a cell receptor, endothelium receptor-A, as well as its ligand -- the protein that binds to the receptor. This discovery means that a small molecule that blocks the ligand from binding to its receptor might tamp down production of mitochondrial ROS, thus halting damage to the glomerulus, Dr. Daehn says. The researchers used an experimental small molecule, BQ-123, to specifically block this receptor and found that mice that were destined to develop diabetic kidney disease were spared from the disorder. Researchers tested their hypothesis by looking at urine and kidney biopsies from patients with diabetic kidney disease. They found molecules in the urine linked to oxidative stress and rapid disease progression, and biopsies that showed increased mitochondrial DNA damage and increased endothelium receptor-A expression. "These findings in human samples go a long way to substantiate our hypotheses, which is exciting because it represents a new way forward to understanding and treating diabetic kidney disease," Dr. Daehn says. Among other researchers from the Icahn School of Medicine who co-authored the study was senior investigator Erwin Böttinger,, MD, Professor of Medicine (Nephrology). The research team also includes investigators from Columbia University in New York and the University of Gothenberg in Sweden. The study was supported by National Institutes of Health Grants 5U01DK060995, 5R01DK056077 and R01DK097253. The authors report no conflicts of interest. The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care. The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals." For more information, visit http://www. , or find Mount Sinai on Facebook, Twitter and YouTube.
News Article | October 26, 2016
Ground-breaking work on synthetic organ transplants made Paolo Macchiarini one of the most famous doctors in the world. But some of his academic research is now seen as misleading, and most of the patients who received his revolutionary treatment have died. What went wrong? In July 2011, the world was told about a sensational medical breakthrough that had taken place in Stockholm, Sweden. The Italian surgeon Paolo Macchiarini had performed the world's first synthetic organ transplant, replacing a patient's trachea, or windpipe, with a plastic tube. The operation promised to reshape organ transplantation. No longer would patients have to wait for a donor organ, only to run the risk of biological rejection. Plastic tracheas - and possibly other organs - would be produced quickly, safely, and made-to-measure for each patient. It was a story that befitted the reputation of Dr Macchiarini's workplace, the prestigious Karolinska Institute, whose professors decide each year who will receive the Nobel Prize in Medicine. But five years on, Macchiarini's headline-making work has brought KI and its sister organisation, the Karolinska University Hospital, no glory. Of the nine patients that received the treatment, in Sweden and elsewhere, seven have died. The two still alive have had their synthetic tracheas removed and replaced with a windpipe from a donor. Last week, an independent report sharply criticised the three synthetic trachea operations that took place at Karolinska University Hospital. The investigation, led by Kjell Asplund, Chairman of the Swedish Council on Medical Ethics, found that the scientific foundation for the new operation was weak, and condemned the failure to carry out risk analyses before the patients received their operations, or seek the necessary ethical approval. On Monday, a separate investigation at KI identified mistakes made when Macchiarini was recruited and when allegations of misconduct were made against him two years ago. In the picture that emerges from these reports, we see a doctor persisting with a technique that showed few signs of working and able to take extraordinary risks with his patients, and a medical institution so attached to their star doctor that they ignore mounting evidence of his poor judgement. Macchiarini arrived in Stockholm in 2010, already a leader in the field of regenerative medicine - the project of growing tissue or organs to be implanted in sick patients. Not only was Macchiarini known as a brilliant surgeon, he was handsome and impressive - able to give press conferences in several languages. At the hospital, a "bandwagon effect" emerged around his work. "Regenerative medicine" was at the cutting edge of scientific fashion, and few colleagues raised questions or objections about the basic science underlying the procedures. The patient who received that first synthetic organ transplant, in 2011, was 36-year-old Andemariam Beyene, a graduate student from Eritrea living in Iceland. After unsuccessful treatment for a rare form of cancer, he had been referred by his Icelandic doctors to the experts at Karolinska University Hospital. Macchiarini told Beyene that the revolutionary surgery was his only chance of survival and persuaded him to agree to the new procedure. The synthetic "scaffold" for Beyene's new trachea was made in a lab in London. It was seeded with stem cells taken from the patient's bone marrow, then placed in a shoe-box sized machine called a bioreactor, where it rotated in a solution designed to encourage cell growth. The idea was that these cells would divide and turn into tracheal cells. Before the operation, Macchiarini also deposited slivers of cells from the patient's nose on the scaffold. It was hoped these would grow into a lining of epithelial cells. In effect, the doctors were trying to grow a new trachea inside Beyene's body. A month after the operation, reporters from around the world were able to interview Beyene in bed. He told the BBC: "I was very scared, very scared about the operation. But it was live or die." By the end of the year, Macchiarini and his colleagues were writing in the Lancet that Beyene had an "almost normal airway" that was free of infection and growing new tissue. The publication of this sent a signal to the medical community that the miraculous-sounding project of growing and implanting synthetic transplants was a viable treatment. By this time, two more synthetic tracheas had been implanted. In the first - an operation not overseen by Macchiarini - a young British woman in a serious condition received a trachea at University College London. In the second, Macchiarini himself fitted a 30-year-old American man with a new kind of scaffold. These two patients only survived for a few months. No autopsy was performed on the American man so his exact cause of death is unknown, but we know that the British woman's synthetic trachea did not function well. "The biggest problem with the materials used at that time was lack of integration into the surrounding bodily tissue, both outside it and at the ends where you join it on to the bronchi and the larynx," says one of the surgeons, Prof Martin Birchall at UCL. "At those junctions it always seems to be loose and healing tissue can become an obstruction to breathing. "The second thing that seemed to happen was that you are putting the trachea on to a bed, which is made up of the oesophagus, the swallowing tube, and the synthetic material could press into the oesophagus. "Finally, the lining didn't seem to grow into the scaffolds either, so you are left with something chronically infected and unable to clear mucus properly." The patient was able to go home after the operation, but died two months later. Over the next three years, Macchiarini implanted six more synthetic tracheas, and four of these patients died. It is unknown whether their deaths were all related to the tracheas, or whether they were due to underlying illnesses or even unrelated events. Karolinska University Hospital stopped Macchiarini's work in November 2013, but he continued to perform the transplants as part of a clinical trial in Russia. Meanwhile, reports about the health of the first patient, Andemariam Beyene, remained positive. In a 2014 article published in the Journal of Biomedical Materials Research, Macchiarini reported that he had an "almost normal" airway a year after the operation, repeating the phrase from the Lancet article. But by the time that article appeared Beyene too had died. He had suffered repeated infections, and his trachea needed to be held open by a series of stents. His autopsy revealed the synthetic trachea had come loose. However, the questions that have dogged Paolo Macchiarini are related less to disappointing patient outcomes, and more to the decision-making around operations. Had the risk of each operation been properly assessed? Were the patients ill enough to require such drastic intervention? Did the patients understand the risks involved? Then there is a second set of questions that relate to the way Macchiarini has described the operations in academic publications. After Beyene's death, four doctors at the Karolinska Institute began to have doubts about synthetic transplants, and about Macchiarini himself. The group included Karl-Henrik Grinnemo, who had assisted Macchiarini in Beyene's organ transplant operation in 2011, and Thomas Fux, who was involved in the aftercare of Macchiarini's patients at the hospital. They alleged that Macchiarini had misrepresented the success of the operations, omitting or even fabricating data in his published articles. KI's vice chancellor at the time, Dr Anders Hamsten, called in an outside expert, Dr Bengt Gerdin, from Uppsala University Hospital, to lead an investigation. In May 2015, Gerdin reported back, concluding that by-and-large the whistleblowers were right: Macchiarini was guilty of scientific misconduct. But in August 2015 Hamsten and the KI management threw out Gerdin's report. Based on undisclosed evidence they had seen - which Gerdin had not - they reaffirmed their faith in the surgeon and extended his contract. In the end, it was not a scientist, doctor or lawyer that grounded Macchiarini's high-flying career, but a TV journalist. Bosse Lindquist followed the surgeon for months for a documentary series for the Swedish public broadcaster, SVT. Lindquist also scoured the world's media archives for footage of Macchiarini, and he was rewarded with a wealth of material. "It turned out that Macchiarini had always liked journalists and had often invited TV teams to his surgeries," Lindquist says. Some of the most striking moments of the series come from these archive rushes. For example, Lindquist uncovered footage of Andemariam Beyene undergoing bronchoscopies, the procedure in which doctors view a patient's airways with a miniature camera. The footage from the surgical camera seemed to conflict with the descriptions of the patient in Macchiarini's published articles. Instead of an "almost normal airway" the footage showed that a build-up of scar tissue was impeding the passage of air to the right lung. The clips also showed a fistula - a hole into the rest of the body - at the end of the trachea. The articles are currently the subject of yet another investigation. On Friday, the Central Ethical Review Board in Sweden ruled that a 2014 article by Macchiarini, published in the journal Nature Communications, involved research misconduct. The article described a transplant trial in rats, which, the committee ruled, was not as successful as had been implied. The Review Board will rule on the other contentious articles soon. The 2011 article in the Lancet now carries an "expression of concern". The senior editor of the Journal of Biomedical Materials Research tells the BBC that his journal will issue a similar warning soon. Macchiarini says that some mistakes were made in the preparation of the articles, but there was no intention to mislead. Lindquist agreed not to ask Macchiarini about the allegations against him until the outcome of KI's internal investigation in 2015, but eventually the two men sat down for a long and very awkward interview. The normally urbane Macchiarini becomes increasingly rattled as Lindquist presses him to answer why five human beings received plastic tracheas before any experiments checking the suitability of the scaffolds in animals were published. At first, Macchiarini says that his team conducted animal studies before 2011 at KI, but they have yet to be published. When Lindquist points out that he has found no official approvals for such research, Macchiarini changes tack, asking, "How do you know that we didn't do animal studies in Russia?" Finally the doctor admits in an irritated tone, "We didn't do any animal study that involves large animals - of course not, we didn't have the time. The material was proven, the material was studied. We used fibres that were approved by the FDA [the US Food and Drug Administration]. And now all the studies are coming." Lindquist called his documentary series The Experiments. The implication is that Macchiarini was treating humans as guinea pigs, instead of doing preliminary research on animals. When it was broadcast in Sweden in January, The Experiments caused a sensation, with about 15% of the population tuning in to watch this complicated medical story unfold. Anders Hamsten stood down as vice-chancellor of KI, as did Urban Lendahl, the general secretary of the Nobel Committee. Macchiarini was fired, and half a dozen inquiries launched. Last week, the Swedish government sacked all members of KI's board who remained in position. Bo Risberg, professor emeritus of surgery at the University of Gothenberg and a former chairman of the Swedish Ethics Council, has called for the Nobel Prize to be suspended for two years as an "apology" to Macchiarini's patients and their families. He has said the events amount to the biggest research scandal Sweden has experienced in modern times. "It is very strange that it should take a TV programme to make this public," Risberg said earlier this year. "Everything was swept under the carpet." The failure to do pre-clinical tests on animals, he said, was "the worst crime you can commit." In May, Macchiarini discussed his decision to operate on Andemariam Beyene on SVT. "We had a human being that we wanted to save," he said, "And in these circumstances what would you do? Do you just leave him dying at that young age? I don't think it's correct." This touches on the blurred distinction between trying out a new treatment as part of a clinical research programme, and innovating in an emergency to save or prolong a life. The Swedish government is investigating whether guidelines differentiating the different scenarios need to be clearer. Last week's report into the synthetic transplant operations that took place at Karolinska University Hospital concluded that while there was a compassionate element to the operations, they still involved clinical research. Therefore, Macchiarini should have sought approval from an ethical review board. "It is unlikely that the project would have been approved," the report notes. Moreover, it states that there was no immediate threat to life for Macchiarini's three patients before the operations. In an email to the BBC, Macchiarini says he accepts the findings of the report, but he adds that it was the responsibility of the hospital administration to apply for ethical permissions. "I would welcome international discussion and clarification of the ethical processes to be undertaken in such difficult circumstances as these - where experimental treatments are involved," he writes. "It is clearly a difficult area for clinicians and researchers to be involved in, and yet vitally important that new treatments are developed and tried…" Macchiarini says that the report highlights "the very great amount of pre-clinical research that has been done into synthetic tracheal scaffolds", though he concedes that Andemariam Beyene was the recipient of an untested procedure. "I would like to add that the welfare of patients has always been my driving concern. Although there may be criticisms of decision-making processes and administrative processes, and these may have had tragic consequences that with hindsight are deeply regrettable, everyone involved in the clinical care of these patients felt that they were doing their very best for these individuals. That should never be overlooked." When asked about the transplants, Macchiarini has often mentioned that he was not the only one responsible for the decision to operate, but discussed his patients in multidisciplinary conferences. "There were 30 or more professionals involved in the decision-making process," he told SVT, "and then even in the inter-operative and postoperative care of the patient." Yet one of the most critical issues was not discussed in the meetings - whether there was enough scientific evidence to support the procedure. Some experts claim that the entire project of growing human organs, although appealing to popular science journalists, is flawed. Dr Pierre Delaere, a professor of respiratory surgery at KU Leuven in Belgium, has said that it is impossible for surgeons to establish a new blood supply to a trachea - donated or synthetic. Delaere has called Macchiarini's method "one of the biggest lies in medical history, because you are doing something that is impossible from a theoretical point of view". The use of bone marrow cells has also come under scrutiny. "There is absolutely no evidence that these cells differentiate into mucosal epithelia (lining tissue) or blood vessels," says Leonid Schneider, a science blogger who trained as a molecular cell biologist and used to work in stem cell research. "This claim that bone marrow cells can create any kind of tissue is based on old papers, which are long discredited by science, and every single stem cell scientist will tell you they cannot do it." He adds: "Everybody switched off their brain. The stem cell scientists switched off their brains to the science, and the clinicians switched off their brains to the use of the plastic, which couldn't even be sutured into patients, and everybody went along with it." Macchiarini maintains, in his email to the BBC, that "there is no doubt that it is a viable technology". He adds that he is continuing his work with biological scaffolds, expanding his focus from the trachea to other organs. A public prosecutor in Stockholm is currently gathering as much information as she can about the three operations that took place at Karolinska University Hospital, and says she will decide next year whether to press charges equivalent to manslaughter and grievous bodily harm. The hospital is already the subject of two police investigations, triggered last year by complaints from government healthcare agencies. Despite his many appearances in the media, the man at the centre of the scandal remains something of an enigma. By chance, the transmission of The Experiments in Sweden coincided with the publication of an article in Vanity Fair in which it was alleged that Macchiarini had had a relationship with a television producer who was making a film about him. The story alleged that the producer had ordered her wedding dress before learning that Macchiarini was married with children. Macchiarini has declined to comment on the story. "He's an exceptional person for sure, and he has this faculty for stretching the truth just the right amount," says Bosse Lindquist. "But in order to be able to seduce the medical community you need to have a whole host of professors who would like to be seduced and who would like to believe that the Nobel prize is very close, or you can make lots of patent money, for example, or corporate money. "I think he has an acute ability to suss out the faults and cracks in the system where he could manoeuvre." Additional reporting from Christine Westerhaus. Listen to Christine Westerhaus's report on the Macchiarini scandal, which was originally broadcast in February 2016 on the BBC World Service. The Experiments will be broadcast in the UK in BBC4's Storyville strand in October. 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