Jan 22, 2019

Interview with Dr Sylvia Ortega

We have interviewed last week Dr. Sylvia Ortega Martinez, a passionate Spanish neuroscientist.

She got her international PhD in Neuroscience at Universidad Autónoma de Madrid (July 2013). Her research interest is the role of the new neuron formation in a specific brain area (known as Adult Hippocampal Neurogenesis (AHN)), as a key target in neurodegenerative and neuropsychiatric diseases. Indeed, her research experience in six different countries (Spain, USA, Germany, UK, France and Finland) and top institutions (Instituto Cajal, Washington University, Leibniz Institute for Age Research, Oxford University, Universite of Bourgogne, Turku Centre of Biotechnology and The University of Chicago) were focused on this brain process. From July 2017, she is working at The University of Chicago as a postdoctoral researcher in the laboratory of Dr. Sisodia. Her current project aims to elucidate the role of microglia in Alzheimer´s disease through its influence in AHN.

In addition, Dr. Ortega-Martinez is an enthusiastic of science divulgation. Indeed, she has participated in Clubes de Ciencia, Soapbox Science, and has given multiple interviews in newspapers or radio. She is grateful for the opportunity ARJ is given her to talk about science.

ARJ: Could you please do a brief introduction of your research?

Currently my project pursue to elucidate the role of microglia in Familiar early onset Alzheimer´s disease. Specifically, I am interested to understand how microglia affects the new neuron formation in the brain, or neurogenesis, in Alzheimer´s conditions. We already known that mice with specific mutations of Alzheimer´s disease shown lower neurogenesis compared with control mice, after environmental enrichment conditions. We are trying to understand now if microglia has an underlying role in this final output. This research could have a potential future impact in Alzheimer´s disease understanding.

Feb 26, 2018

Efforts to combat A. Baumannii Infections: Meropenem Added to Colistin study results

According to a researched report in The Lancet Infectious Diseases, the addition of meropenem to colistin provides no additional therapeutic benefit to patients suffering with A. baumannii or other carbarpenem-resistant bacteria. This question was the focus of a random trial covering three countries on an open-label, controlled basis. While studies conducted prior to the start of this one showed a boost to bactericidal activity when it came to polymyxin-carbapenem combinations, this further study contradicted those findings for those with gram-negative bacterial infections.

The study orchestrated by Mical Paul, MD, the director of infectious diseases at Rambam Health Care Campus and associate professor in Haifa, Israel, showed these results. His study included hundreds of people in hospital settings.
He and his colleagues also working on this research reported no observances that lead to stating that the combination therapy improved or changed survival rates, microbiological or clinical cure rates, or improved levels of resistance to the bacteria. Since the study primarily dealt with A. baumannii, they did note that other non-dominant bacterium such as Klebsiella pneumonia or Pseudomonas aeruginosa could have different results.

They also concluded that since carbapenem resistance increases with carbapenem use, the overall recommendation dissuades practitioners from using it to battle A baumannii and other infections known to become resistant. While other bacterial infections did not show the same levels of resistance, they stress the importance of increased randomized trials for various combination therapy regimens before they become commonly used in the industry.

Resistance rates for gram-negative bacteria strains grow all around the world. The CDC in the USA has coined the phrase "nightmare bacteria" for Enterobacteriaceae, one type that is highly resistant to carbapenem therapy. The remaining effective treatment combines colistin and polymyxin B, though there is some worry about building resistance in the face of few other treatment choices.
Paul and his colleagues echo this concern. They state that physicians in general are not confident about using polymyxin to counteract carbapenem-resistant, gram-negative bacterial infections. Mortality rates remain high, which drives more researchers to seek out the best possible antimicrobial combinations to combat these strains.

The 406 people involved in the afore-mentioned research study conducted by Mical Paul et al were from Italy, Greece, and Israel. Each had either bacteremia, urosepsis, or ventilator-associated or hospital-acquired pneumonia. Each illness had carbapenem-resistant, gram-negative bacteria at its source. In the majority of cases, that bacteria was A. baumannii.

The research gave a random selection of these patients either colistin monotherapy or colistin in conjunction with meropenem. Data was collected between October 1, 2013 and December 31, 2016. After 14 days after randomized treatment, the most common outcome was clinical failure.
This failure consisted of a 79% rate in the colistin monotherapy group and a 73% rate in the combination group. These close clinical failure rates indicate no sufficient benefit for the addition of meropenem to the therapy regimen. Combination medications did decrease how many patients experience mild renal failure but increased the chance of diarrhea as a side effect.

Similar findings were highlighted by Robert A. Bonomo, MD and Federico Perez, MD (both working at the Case VA Center for Antimicrobial Resistance and Epidemiology and Case Western Reserve University School of Medicine). They indicated two previous controlled studies of people similarly affected by carbapenem-resistant A. baumannii bacteria. Those patients received either colistin by itself or colistin with rifampicin. An additional small study was done with monotherapy or colistin combined with fosfomycin.
Although none of these randomized research trials shone a light on combination therapy that provided exceptional or considerable benefits, Bonomo and Perez feel it important to continue researching combinations. In the face of bacteria such as A. baumannii and others that are resistance to carbapenem, the medical community needs more data on how combination therapy affects different phenotypes or genotypes of bacterium.

Sep 14, 2017

Medical Research's Future Boosted by Changes in Clinical Trials

Amid all the upheaval you see on the news, the fact that a revolution in science is going on may slip by unnoticed. The biomedical community has long been expressing concerns over how reliable various published studies are. The complaints involve the failure to repeat the research outcomes when scientists attempt to reproduce them independently. This has led to a new paradigm for scientific research sharing and availability. Initiatives have been introduced to open up science to the public and make all research freely accessible. The goal? The scientific community feels that, since the data can be accessed by anyone, it will be better understood and believed. Also, other scientists can use the data to fuel other projects funded by the public and other sources.

One of the most iconic examples of this research reform is the introduction of the Registered Report, which is a type of article published in a journal to represent their commitment to publish studies with both positive and negative outcomes. Although it may seem logical to share all information gathered despite the outcome, competition in the science industry and academic world has thus far made it an irregular practice.

Clinical Trial Negatives

Any scientific pursuit is affected by human error. Among all types of studies, clinical trials are those most often believed to be the most reliable. These occur near the end of the research process and often have life or death consequences in the medical community. A clinical trial has always been the last test of a new pharmaceutical or treatment method before it is dubbed effective and safe for human use. Trials are conducted with two groups of patients: one the control group who receives a facsimile treatment or a placebo and one who is given the real thing. No participants know which group they are in. The people conducting the study are also ignorant of each participant's group. Before the research starts, the study must be registered publicly and the data analysis method put into place. This transparent reporting is meant to prevent the scientists from seeing what they want to see instead of what is actually happening. Even with these safeguards, clinical trials suffer from the pressure put on researchers to "publish or perish." What should be the ultimate example of scientific truth may hide hidden agendas.

Are modern science practices fixing the problems of the past?

Although scientific journals do not trouble themselves with entertainment as much as a commercial magazine, the people who read them still want a good story. This publication bias makes certain research results more publishable than others, even if the study was conducted similarly and the outcome good. Take, for example, an imaginary study attempting to prove that a new treatment is more effective against a certain disease than the existing protocol. After careful blind research, the outcome is proven true. The news of a brand-new successful treatment is very exciting and medical journals will be overjoyed to publish this news. The study orchestrators may even find they can place the work in a highly prestigious publication, and, in turn, propel their academic career skyward.

On the other hand, if the research proves that the new treatment did not make any noticeable difference to those afflicted by the disease when compared with current treatments, the study is said to have a negative result. This does not make a good story and therefore may not be published anywhere. It certainly would not attract the attention of international medical journals. For the scientist or group that did the study, funding may be cut off and career trajectory may falter. The negative result studies end up languishing in a file cabinet somewhere and are never shared with the public or scientific community at large.

With this type of outcome for research that does not produce stellar results, scientists are unlikely to make the attempt to get the information out. Instead, they quickly move on to new research that may have a better outcome. The problem with this habit is that negative results are highly useful for the scientific community and necessary to advance the creation of new drugs and medical treatment. It is estimated that anywhere from 16 to 66% of clinical trials are never reported. These high numbers should definitely give pause to those who are interested in a complete and accurate picture.

In the 1980s, a rule about clinical trials was put into place to stop a form of outcome cherry picking. The rule states that all trials should be subject to an advanced registry procedure in which the study design, data collection measures, and plan for analyzation are recorded before any tests are done. The cherry picking that went on prior to this role being put in place may have been done purposefully or as an automatic side effect of simply wanting a positive outcome to a study. How was this accomplished? With a large research study which tests a plethora of variables, scientists could tweak the data collection measures and accepted outcome to achieve a certain result when one did not naturally occur. In layman's terms, they shifted the goalposts in order to achieve a positive outcome. Gotten in this way, an outcome may look positive when it is, in fact, directly opposite.

A researcher's career in the scientific or medical community or the academic world stems from the quality of their research and publications so much so that the bias toward positive outcomes affects their ability to perform a 100% honest study. As mentioned above, this is not always done maliciously. Corners can be cut and expected outcomes tweaked simply to keep their jobs. According to Ben Goldacre's COMPARE project, 58 out of 67 clinical trials reported different outcome measures than the preregistered protocols they had planned or promised to use. Another study in 2014 showed that a full 33% made the same change after study completion.

Registered Reports Offer Double Checks

The old way of doing things does not have the best interest of the public or industry at heart. Luckily, there is a straightforward solution to counteract these hidden changes and the publication bias that makes them so attractive for researchers. The first thing that needs to change is to keep scientific journals ignorant of the outcome of the study until after they deem it publishable or not. In other words, keep them as blind as the clinical trial participants and researchers themselves. Under this system, the study itself must be deemed worthy or not and both negative and positive outcomes will be reported. The second thing that must be enforced is a strict adherence to the outcome data measures that are outlined at the beginning of the research study after the data is collected. If study architects register a certain protocol, they must stick to it or give a thorough explanation why and how they were changed.

How can these two things the put into place successfully? The answer is peer review. The introduction of a Registered Report journalistic article covers this admirably. Instead of a one-off like regular science articles, these have a two-step process. People who will conduct studies first submit the information and process description to the journal for feedback, revise it as necessary to satisfy the scientific community at large, and then publish the outcomes after. Every bit of data collected over the course of the clinical trial or another study must be available to the public for this to work.

There are other specific journals conceived as a way to combat the inability to reproduce outcomes in scientific fields (as The All Results Journals). No longer are researchers controlled by the publication bias and silently encouraged to cherry pick protocol and data. When positive outcomes are no longer the most valuable information, more data is accessible and can help fuel advancements that much quicker. The All Results Journals make negative outcomes as valuable as positive.

Written by Dr. David Alcantara for The All Results Journals

Aug 23, 2017

Violence against women in EU

Violence against women can be addressed through a fundamental rights lens. It is a violation of human dignity and, in its worst form, it violates the right to life. It is also an extreme expression of inequality on the ground of sex. Violence against women exists in every society, and encompasses different forms of physical, sexual and psychological abuse. However, despite its scale and social impact, it remains largely under-reported and relatively under-researched in key áreas.
Women can perpetrate violence, and men and boys can be victims of violence at the hands of both sexes, but the results of many researches, together with other data collection, show that violence against women is predominantly perpetrated by men.
In most EU Member States, until relatively recently, violence against women – particularly domestic violence – was considered a private matter in which the state played only a limited role. It is only since the 1990s that violence against women has emerged as a fundamental rights concern that warrants legal and political recognition at the highest level, and as an area where State Parties, as those with a duty to protect, have an obligation to safeguard victims.
Figure 1. Phisical and / or sexual partner violence since the age of 15, EU-28 (%)

Figure 2. Phisical and / or sexual non- partner violence since the age of 15, EU-28 (%)

In the EU, 1 in 5 women have been victims of domestic violence. Traditional practices such as bride kidnapping and honour killings are present in the Region. Female genital mutilation has been documented among migrant communities.
Violence against women undermines women’s core fundamental rights such as dignity, access to justice and gender equality. For example, one in three women (33 %) has experienced physical and/or sexual violence since the age of 15. One in five women (18 %) has experienced stalking; every second woman (55 %) has been confronted with one or more forms of sexual harassment.
In some countries like Germany the numbers are shoking: According to the Federal Criminal Police Office´s figures, in 2015, a total of 127,457 people in relationships were targets of murder, bodily harm, rape, sexual assault, threats and stalking. Eighty-two percent, or over 104,000, of these were women.
Among the women, over 65,800 suffered simple injuries, 11,400 were badly injured, 16,200 were subjected to threats and nearly 8,000 were victims of stalking. 331 women were killed intentionally or unintentionally by their partners. The fact that so many cases of deaths in the world from gender-based violence continue in 2017 is certainly the least alarming. According to the World Health Organization in its First World Report on Gender Violence published on June 20, 2013, warns that more than a third of all women in the world are victims of physical or sexual violence, wich is a similar health problem in proportion to an epidemic. And it is, in fact, an epidemic since it is present in all areas of the planet, regardless of culture or religion.
The figures show that 38% of women murdered in the world are the result of gender-based violence in hands of their partner, and 42% of those who suffered physical or sexual violence suffered serious health consequences. According to the first World Report on Gender Violence, the situation by region of women would be as shown in the following WHO map:
According to Sánchez in the period between 2004 and 2014 in Spain and Portugal, the situation was the following number of women murdered as the result of gender-based violence in hands of their partner:
Obviously, what stands out most are the data of the deaths of Spain that far exceed those of Portugal. This is due, in part, to the fact that the population of Spain is far superior to that of Portugal. Specifically, on March 29, 2014 the population of Spain was 47,188,680 inhabitants, with 23,878,736 women, or what is the same, 50.6% of its population. On the other hand, Portugal has 10,751,917 inhabitants and of these, 5,542,254 are women, that is, 51.5% of its population.
Given this, violence against women cannot be seen as a marginal issue that touches only on some women’s lives. Yet the scale of violence against women is not reflected by official data. Women generally do not report to the police, and they also do not report to a number of other services that could support them, including victim support organisations.
Therefore, a serious and deep approach at the state and institutional levels is urgently needed, especially considering that in the last years the number of women murdered by their partners or ex-partners is so high so the number of cases of victims of violence.

  1. DW (2016) Domestic violence affects over 100,000 women in Germany. On-line on: http://www.dw.com/en/domestic-violence-affects-over-100000-women-in-germany/a-36482282
  2. FRA, E. (2014). Violence Against Women: An EU-Wide Survey. Main Results Report.
  3. Sánchez, M. J. C. (2015). Estudio comparativo entre Portugal y España, de políticas, acciones y discursos en torno a la igualdad de oportunidades para hombre y mujeres.
  4. World Health Organization (2013). Violence against women. On-line on: http://www.who.int/mediacentre/factsheets/fs239/es/
Written by Dra. María José Cabanillas Sánchez for The All Results Journals. 

Aug 31, 2016

A brief overview in Adult Neurogenesis: the most fascinating brain discovery over the last 50 years

Probably one of the most exciting scientific findings of the last 50 years is the discovery that discrete brain regions generate new neurons throughout life, a concept known as adult neurogenesis. Despite the neurogenesis importance acquired nowadays, this emergent concept remained obscure until neurogenesis was found to occur in the brain of adult humans (Eriksson et al., 1998). In fact, until the 1990s the neuroscience field was under the dogma established in the late 19th to early 20th centuries by the most famous Spanish scientist and considered the father of the modern neuroscience, Santiago Ramon y Cajal (1852-1934). Unfortunately, despite his successful work (author of the ‘neuron theory’), Cajal’s observations made think that the nervous system was a non-variable system. Joseph Altman was the responsible of this new concept, publishing a series of works in the nineteen sixties showing evidence for adult neurogenesis in adult rats and cats (for review see Gross, C.G., 2000). Last year, the neuroscientific community celebrated the 50 anniversary of adult neurogenesis discovery.

Adult neurogenesis involves cell proliferation, survival, migration, and cell differentiation. This process occurs due to the cells that have this proliferative feature, named as Neural Stem Cells (NSCs). Neurogenesis, or the new neurons generation, was traditionally understood to be mainly an embryogenetic phenomenon, but research in the field has shown the existence of neural cells generation in several areas of the adult brain. These areas include the Dentate Gyrus (DG) in the hippocampus, subventricular zone (SVZ) around the lateral ventricles, olfactory bulb (OB), and other brain places where it was recently described such as the cortex, amygdala or hypothalamus, among other. However, in these last regions, neurogenesis function remains unclear (Gould, 2007; Ortega-Martinez, S. 2015) (Figure 1):

It was the use of a tritiated Thymidine analogue, Bromodeoxyuridine (BrdU), used as a proliferation marker, which allows the scientists to discover this exciting finding. BrdU can easily be labeled with immunohistochemical methods and investigated with a bright filter and fluorescence microscopy. In addition, specific antibodies against neuronal or glial markers were developed, providing easy methods to distinguish neurons from glia. Between the most relevant markers in the study of neurogenesis, it is possible to highlight the widely use of Sox2+/GFAP+ to label precursor or Neural Stem Cells (NSCs) (Type 1 cells), MCM2 for the analysis of amplifying progenitors (Type 2 cells), DCX to label neuroblasts/ immature neurons (Type 3 cells), and NeuN or Prox1 to distinguish mature neurons, among other. With the help of these methods, adult neurogenesis has been demonstrated to exist until senescence in numerous mammalian species including humans (Eriksson, 1998). Finally, the neuronal behavior of these new cells and their integration into the network was confirmed by experiments testing long-term potentiation (LTP), synapse formation and expression of immediate early genes after stimulation of the hippocampal network (Kempermann et al, 2003; Song et al, 2002; H.Van Praag et al, 1999).

The study of adult neurogenesis has been made at different levels. Indeed, in vivo models have been used aimed the neurogenesis removal such as for example X-ray (Saxe MD et al, 2006) or using transgenic models (as used by Jin K et al, 2010). In addition, this process has been analyzed through NSC in vitro culture. Nowadays, specific techniques to label these nascent neurons have emerged. In this regard, neurogenesis field has improved, a lot of thanks to the use of retrovirus (Zhao et al, 2006), which specifically infect cells in division allowing the visualization of these nascent cells along the route to neurogenesis (figure 2):

The essential neurogenesis area of research is the dentate gyrus of the hippocampus, named as Adult Hippocampal Neurogenesis (AHN). Since the general recognition and acceptance of AHN in the scientific community, many studies have been conducted to investigate how neurogenesis is regulated. Nowadays it is known that AHN is a process highly regulated by multiple factors such as hormones, growth factors, neurotransmitters, etc. (see Ortega-Martinez, 2015). AHN is extensively studied due to its important brain functions. In this sense, AHN has been widely described as occurring at the level of the subgranular zone (SGZ) and has been shown to contribute to learning and memory (Cameron et al, 2015; Fanselow et al, 2010), mainly in the dorsal hippocampus. AHN involves not only new neuron formation but also the integration of these new-born neurons into functional networks, making the process as a functional one. From this perspective, AHN facilitates memory consolidation via formation of networks (Deng et al., 2010; Weisz and Argibay, 2012; Ortega-Martinez, S. 2015). Furthermore, AHN provides plasticity required in memory processes and allows for ‘‘pattern separation mechanisms’’ which is crucial for memory consolidation (Bruel- Jungerman et al., 2007; Sahay et al., 2011; Bekinschtein et al., 2011; Yassa and Reagh, 2013; Ortega-Martinez, S. 2015).
In contrast, the ventral hippocampus has been related to emotional functions (Fanselow et al, 2010), involved in processes such as stress, depression, and anxiety. A great number of studies have demonstrated the relationship between hippocampal neurogenesis, stress, and depressive disorders (McEwen et al, 2001; Sapolsky, 2003). Consequently, AHN has been postulated as a key factor in these processes (Jun et al, 2012; Petrik et al, 2012) (Figure 3):

Basic and clinical studies demonstrate that depression is associated with reduced size of certain brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and a decreased number of neuronal synapses is observed in these areas (Duman et al, 2012). In the 1990s it was discovered that stress and stress hormones robustly decrease the generation of hippocampal neurons and increase cell death (Gould et al, 1992). It was also found that depletion of serotonin inhibits adult neurogenesis and that chronic, but not acute, antidepressant treatment increases SGZ proliferation and neurogenesis (Brezun et al, 1999; Malberg et al, 2000).

Thus, ‘The neurogenesis hypothesis of depression’ was coined, by which the recuperation of depressive symptoms are associated with an increase in AHN (Eisch et al, 2012). Later work has confirmed the association between hippocampal plasticity and stress (McEwen et al, 2001; Hirschfeld, R.M, 2000; Mahar et al, 2014). Even though the role of AHN in stress and anxiety is to some extent accepted, the molecular mechanisms involved in the regulation of these processes remain poorly understood.

In addition, there is extensive evidence for altered neurogenesis in neurodegenerative diseases such as Alzheimer’s disease (Mu et al, 2011). The memory loss of Alzheimer disease patients is related to a disturbed neurogenesis in the hippocampus, and hippocampal neurogenesis would constitute a potential target for therapy. The compensation for neuron loss in the hippocampus by controlled stimulation of endogenous neurogenesis might restore some of the lost hippocampal function (Mu et al, 2011).

Summary: adult hippocampal neurogenesis is extensively considered essential in memory and emotional processes. Numbers of papers related to neurogenesis and learning have exponentially increased since AHN discovery, 50 years ago (see Ortega-Martinez, S., 2015). Even recently, adult neurogenesis process has been described to occur in more brain areas, the link between memory and related neurogenesis primarily occurs in the DG of the hippocampus and OB. By the other hand, the adult hippocampus has been widely studied for its implications in numerous neurodegenerative and neuropsychiatric disorders, such as depression, anxiety, or Alzheimer´s disorder, among others. All these brain disorders also share, between other physiological features, its decreased AHN. In fact, and because hippocampus-dependent memory processes are altered in such diseases, understanding the underlying molecular mechanisms is important for restoring normal brain function. Indeed, some recent drug discovery efforts have focused on increasing AHN (Ortega-Martinez, S., 2015). To reach this functional ‘in vivo’ increase in hippocampal neurogenesis within the human brain, constitutes nowadays, an essential key target in neuroscience, for the future advance and development of new treatments for brain disorders, with all the societal and economic implications associated.

Bekinschtein, P. ,Oomen, C.A., Saksida, L.M.,andBussey, T.J (2011). Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory and pattern separation: BDNF as a critical variable? Semin. Cell Dev. Biol. 22: 536–542.doi:10.1016/j.semcdb.2011.07.002

Brezun, J.M.; Daszuta, A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89, 999-1002 (1999). 

Bruel-Jungerman, E.,Rampon,C.,and Laroche,S.(2007). Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev. Neurosci. 18: 93–114. 

C. Zhao, E. M. Teng, R. G. Summers, Jr., G. L. Ming, and F. H. Gage, 'Distinct Morphological Stages of Dentate Granule Neuron Maturation in the Adult Mouse Hippocampus', J Neurosci, 26 (2006), 3-11. 

Cameron, H.A.; Glover, L.R. Adult neurogenesis: beyond learning and memory. Annual review of psychology 66, 53-81 (2015). 

Deng, W., Aimone, J.B., and Gage, F.H (2010). New Neurons and New Memories: How Does Adult Hippocampal Neurogenesis Affect Learning and Memory?. Nat Rev Neurosci, 11: 339-50. 

Duman, R.S.; Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68-72 (2012). 

Eisch, A.J.; Petrik, D. Depression and hippocampal neurogenesis: a road to remission? Science 338, 72-75 (2012). 

Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H (1998). Neurogenesis in the Adult Human Hippocampus. Nat Med, 4: 1313-7. 

Fanselow, M.S.; Dong, H.W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7-19 (2010). 

Gould, E. (2007). How Widespread Is Adult Neurogenesis in Mammals?. Nat Rev Neurosci, 8: 481-8. 

Gould, E., Cameron, H.A., Daniels, D.C., Woolley, C.S.; McEwen, B.S. Adrenal hormones suppress cell division in the adult rat dentate gyrus. The Journal of neuroscience : the official journal of the Society for Neuroscience 12, 3642-3650 (1992). 

Gross, C.G. (2000). Neurogenesis in the Adult Brain: Death of a Dogma. Nat Rev Neurosci, 1: 67-73. 

Hirschfeld, R.M. Antidepressants in long-term therapy: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta psychiatrica Scandinavica. Supplementum 403, 35-38 (2000). 

Jun, H., Mohammed Qasim Hussaini, S., Rigby, M.J. & Jang, M.H. Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders. Neural plasticity 2012, 854285 (2012). 

K. Jin, X. Wang, L. Xie, X. O. Mao, and D. A. Greenberg, 'Transgenic Ablation of Doublecortin-Expressing Cells Suppresses Adult Neurogenesis and Worsens Stroke Outcome in Mice', Proc Natl Acad Sci U S A, 107 (2010), 7993-8. 

Kempermann G., Jessberger S, (2003). Adult-Born Hippocampal Neurons Mature into Activity-Dependent Responsiveness. The European journal of neuroscience, 18: 2707-12. 

Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M., and Gage, F.H. (2003). Early Determination and Long-Term Persistence of Adult-Generated New Neurons in the Hippocampus of Mice. Development, 130: 391-9. 

M. D. Saxe, F. Battaglia, J. W. Wang, G. Malleret, D. J. David, J. E. Monckton, A. D. Garcia, M. V. Sofroniew, E. R. Kandel, L. Santarelli, R. Hen, and M. R. Drew, 'Ablation of Hippocampal Neurogenesis Impairs Contextual Fear Conditioning and Synaptic Plasticity in the Dentate Gyrus', Proc Natl Acad Sci U S A, 103 (2006), 17501-6. 

Mahar, I., Bambico, F.R., Mechawar, N.; Nobrega, J.N. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neuroscience and biobehavioral reviews 38, 173-192 (2014). 

Malberg, J.E., Eisch, A.J., Nestler, E.J. & Duman, R.S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 20, 9104-9110 (2000).

McEwen, B.S. & Magarinos, A.M. Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Human psychopharmacology 16, S7-S19 (2001). 

Mu, Y. ; Gage, F.H. Adult hippocampal neurogenesis and its role in Alzheimer's disease. Molecular neurodegeneration 6, 85 (2011). 

Ortega-Martinez, S. (2015). A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci. 8(46). DOI: 10.3389/fnmol.2015.00046 

Ortega-Martinez, S. (2015). Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis. Behav. Brain Res. 281: 309–317. 

Petrik, D., Lagace, D.C. & Eisch, A.J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21-34 (2012). 

Sahay, A., Wilson, D.A., and Hen, R (2011). Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb. Neuron, 70: 582-8.

Sahay,A.,Scobie,K.N.,Hill,A.S.,O’Carroll,C.M.,Kheirbek,M.A.,Burghardt,N.S.,etal.(2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472: 466–470 

Sapolsky, R. Taming stress. Scientific American 289, 86-95 (2003). 

Song, H., Stevens, C.F., and Gage, F.H (2002). Astroglia Induce Neurogenesis from Adult Neural Stem Cells. Nature, 417: 39-44. 

Van Praag, H., Kempermann, G., and Gage, F.H (1999). Running Increases Cell Proliferation and Neurogenesis in the Adult Mouse Dentate Gyrus. Nat Neurosci, 2: 266-70.

 Weisz, V.I., and Argibay, P.F.(2012). Neurogenesis interferes with the retrieval of remote memories: forgetting in neurocomputational terms. Cognition 125(1): 13-25.

 Yassa, M.A., and Reagh, Z.M (2013). Competitive trace theory: a role for the hippocampus in contextual linterference during retrieval. Front. Behav. Neurosci. 7:107.  

Written by Sylvia Ortega-Martínez for The All Results Journals. The author acknowledges Marie Curie fellowship and Åbo Akademi University for supporting Dr. Sylvia Ortega-Martinez. Dr. Sylvia Ortega-Martínez received a postdoctoral fellowship from the FP7 Marie Curie ITN r’BIRTH.

Aug 29, 2016

Satellite cells do not mediate zebrafish extraocular muscle: when an initial negative result guides you to a more scientifically relevant finding

Degenerative and atrophic muscle diseases such as muscular dystrophies, as well as extensive muscle damage or loss related to trauma, tumor resections and other conditions, represent one of the most important public health concerns. It is estimated that the combined cost of the relatively uncommon disorders amyotrophic lateral sclerosis, Duchenne muscular dystrophy, and myotonic muscular dystrophy is $1.07 to $1.37 billion per year in the USA. Although global estimates are difficult, the total cost of degenerative and traumatic muscle conditions would be substantially higher. Right now the only available treatments for these pathologies are palliative therapies that do not solve the underlying cause of the disease.

In contrast to mammals, salamanders and fish has the capacity of regenerating complex tissues. Thus, zebrafish has become a popular model to study tissue regeneration because are highly regenerative and very amenable to both forward and reverse genetic approaches. To provide foundational transferable knowledge to develop new pharmacological and therapeutic targets, we have described a new model of muscle regeneration using adult zebrafish extraocular muscles. We found that after amputating 50% of the lateral rectus (extraocular muscle chosen as a proof of principle) zebrafish regenerate an anatomically correct and functional muscle in 7 to 10 days (Fig. 1):

Mammalian muscles are considered post-mitotic meaning that they have completely differentiated in mature muscle cells and will never enter the cell cycle again. Therefore, muscle growth and repair are achieved by myogenic progenitor cells termed satellite cells. Therefore, as a first step to understand the mechanisms that control zebrafish muscle regenerative response we looked for the satellite cells, the usual suspects in these matters. We used Pax7, a transcription factor expressed only in muscle satellite cells, to identify the satellite cells in regenerating muscles (Fig. 2). We were able to find Pax7-positive cells (satellite cells) in somatic muscle, both embryonic (Fig. 2A) and adult (Fig. 2D), and embryonic extraocular muscles (Fig. 2B, C). Surprisingly, we could not detect satellite cells in the extraocular muscles of adult zebrafish, either uninjured (Fig. 2E, F) or regenerating after amputation (Fig. 2 G, H):

Because extraocular muscles satellite cells do not do not express Pax7 in some species, we tried to identify these cells using a different method. Classic satellite cells localize between the basal lamina and sarcolemma of muscle fibers. Thus, we used electron microscopy to identify putative satellite cells following this morphologic criterion. Again, classic satellite cells could not be detected in adult zebrafish extraocular muscles but we identified rare cells that might represent a type of ‘‘post satellite cells’’. These cells are muscle progenitor cells fully encapsulated by the basal lamina described in newts.

Combining the fact that we could not detect satellite cells using their most typical marker, that even these so-called ‘‘post’’ satellite cells in newts express Pax7 and that newt limb regeneration also appears to be mostly independent of Pax7-positive cells we concluded that the regeneration of adult extracellular muscles is not mediated by classic satellite cells.

This initial negative result forced us to elaborate a multidisciplinary research approach (including whole-mount fluorescent imaging, cellular tracing, molecular and histological techniques) to decipher how zebrafish extraocular muscles regenerate after injury. We found a mechanism that goes against the accepted dogma in the muscle biology field that postulates that muscle fibers are post-mitotic and therefore will never enter the cell cycle again.

More details about these results and the following investigations in zebrafish extraocular muscle regeneration can be found in Dr. Saera-Vila scientific papers (http://bit.ly/2bDI3me, http://bit.ly/2bu69Cz and http://bit.ly/2baG5dm)  

Written by Dr. Alfonso Saera for The All Results Journals.

Jun 16, 2016

Could we change the way we design our clinical trials to minimize failures?

We all hear from time to time that clinical trials fail sometimes, but the question today is why do they fail? And why should everyone know when something fails? Could we change the way we design our studies to minimize failures if we know why they fail?

Any regulations set for the clinical trials have a common goal to harmonize the procedures for clinical trials while making sure of the safety of clinical trial volunteers, the ethicality of trials and the dependability and productive effect of data derived. It advocates increasing reliability with regard to clinical trials results, data and their result. For life science companies, clinical trial information is highly of discreet affair which permeates a wide cultural evolution given that they operate in a very systematic and competitive environment, with lots of risk and profit.

The last few years, increasingly noticeable numbers of life science organizations have adopted a more free and transparent policy with regards to the results of their clinical trials, regardless of the positive or negative results.

From the recent past (March 2016) Celldex Therapeutics conducted a clinical trial on a brain tumor vaccine Rintega but the results were fruitless crushing its stocks. The organization announced the failure of Rintega Phase III study known as ACT UV after an interim analysis conducted by independent data monitors. The studies enrolled patients with certain type of Gliblastoma Multiforme (GBM), an aggressive brain tumor. Rintega was found to reduce the risk of death by just 1% compared to the control arm. However, at the median, Rintega-treated patients fared worse, surviving 20.4 months compared to 21.1 months for the control arm. Celldex is discontinuing clinical development of Rintega. Obviously, the company's plans to seek approval for the product in the U.S. or Europe are also being shelved. Celldex has two other drugs being tested on different clinical trials.

Cancer vaccines, particularly those targeting GBM, have a dismal track record. The failure of Rintega follows negative study results for ImmunoCelluar Therapeutics' GBM vaccine ICT-107. Northwest Biotherapeutics is developing a GBM vaccine known as DCVax, but a phase III study has been stalled since August due to an unexplained patient enrollment halt. There are other clinical trial failures too: Chrimex`s stocks also plunged recently after the failure of the clinical trial of an anti-infection drug in Phase III. [Dec-2015]. A French company`s [Bial] drug trial leaves on Brain dead and two others with permanent damage, there is no known antidote as the drug was never used on human before this trial. There is a 50% probability for every clinical trial to fail.

There are three root causes of clinical trial failures:

A. Molecule issues
When the molecule, doesn’t have sufficient biological activity or doesn’t have manageable toxicity. A well-designed clinical program can pick up the side activity and the program can be redirected. But if the molecule has no biological activity when it enters clinical development, only little can be done to salvage it. Just as important are predictability and pervasiveness of the unmanageable toxicity. Every molecule has toxicity but it is important to design a clinical trial accordingly around them.

B. Logistic issues
Half of the published preclinical experiments may be unreproducible. In the hurry to get the clinical trial started, sometimes sponsors neglect to triple-check the randomization algorithm. Despite validation, mistakes in data analysis programming can occur. Many companies don’t double program (have two sets of independent programmers or program two full sets of analysis independently) and in that case, it is almost inevitable there will be mistakes somewhere.

C. Study design issues
Error in clinical trial design is perhaps the most common reason trials fail, other than the above two reasons. There are many variables in clinical trial design but of those, three are the most important when it comes to insuring a successful clinical trial:
  • Selecting the right patients
    • Patient selection can go awry if the selection blindly follow the conventional disease categories and definitions. There are many ways to define patient populations and diseases. It is not always optimal to define the patient population by a previously recognized disease category because disease categories are intellectual constructs
  • Selecting the right dosing
    • All the characteristics of the dose, including: the amount of an intervention administered, the route of administration (e.g., oral, IV, SC), the dosing interval, the rate and duration of administration.
    • Frequently seen error is using a dosing regime that is too undifferentiated, such as a flat dose. When great heterogeneity in patient response or a narrow therapeutic window exists, you may have to customize the dose.
  • Selecting the right endpoint
  • Clinically relevant
  • Closely and comprehensively reflects overall disease being treated
  • Rich in information
  • Responsive (sensitive, discriminating, and has good distribution)
  • Reliable (precise, low variability, and is reproducible) even across studies
  • Robust to dropouts and missing data
  • Does not influence treatment response or have biological effect in and of itself
  • Practical (implementable at different sites, measurable in all patients, economical, and reasonably noninvasive)

Often, a drug has biological activity but it is tested for the wrong indication. Or, it is tested in the right indication but in the wrong sub-populations. In other instances, the wrong dose or dose interval is selected. It is therefore kept in mind that sometimes the most expensive testing studies fail for various reasons leaving long lasting scientific and trading loss.

 http://www.celldex.com/pipeline/rindopepimut.php lhttps://clinicaltrialist.wordpress.com/clinical/why-clinical-trials-fail/

Written by Shalini P. Burra for The All Results Journals. 

Oct 1, 2015

Negative results on cold fusion experiments

What is Cold Fusion?

The dictionary definition of cold fusion is a nuclear fusion occurring at or close to room temperature. It is only a theory at this point in time. It's never actually been proven. There are some claims from people saying they've achieved it but they have all been debunked. We'll delve into that later, this first section is just to get your feet wet. An introduction to get you familiarized with what this energy source is and the benefits we could reap from it if we ever were to successfully prove the theory. 

Imagine if you didn't need to worry about over heating cores at nuclear facilities. If cold fusion were ever actually attained we could basically have the power of a star at room temperature. The main reason it has never been put into actual testing is because of two factors: radiation leaks and long term environmental effects. 

We know that radiation would quite possibly leak out but we have no way of measuring how much and how it would affect us. It would absolutely affect those that work closely with fusion reactors. Who's to say they would be willing to risk their health for an alternative that could potentially provide cheap energy sources to the world? Some of the environmental effects would be longer spring seasons. So plants would grow longer and become more prevalent which would increase pollen and disorient living for those that suffer from allergies. Since the reactors would be a cheap source of energy the influx of toxic waste dumping could sky-rocket. These devices have the potential to create better ways of living in third world countries. They could help provide drinking water. Although, a desalinator would need to be involved as heavy metals, salts, and minerals could form in the water provided.


Negative Results

The hunt to prove this energy source outside of just theories started in 1989. The masterminds behind the tests were Stanley Pons and Martin Fleischmann. They claimed to have proved the theory in a lone test tube with none other than a palladium electrode and heavy water. Physicists everywhere took to their labs and began attempting to replicate the experiment but they all received negative results. Repeatedly, due to the hype over the successful experiment before them and the anxiety created by the possibility it might actually be proven physicists kept trying their hand and bending over backwards trying to have another successful experiment. After so many experiments ended in failure Pons and FLeischmann were called into question by the scientific community. Eventually, their experiment, the only proven experiment was deemed falsified. No one else was able to replicate what they had done and so they were deemed to have fooled everyone into false hopes. 

Research for the scientific version of the holy grail is still continued today. In about eight countries, the search for was not over and done with. Dr. Alexander Borisovich Karabut was one of the scientists who didn't give up hope when Pons and Fleischmann's theory was declared false in the 1990s. Pons and Fleischmann's theory rallied around electrolysis while Dr. Karabut thought the theory might be proven if they went down the path of using plasma. His entire life became a contradictory. His whole education had ingrained in him the simple fact that nuclear energy would not work at low energies. He was determined and sought to prove that it was indeed possible. However, this tenacity would be his downfall. In some of his papers he confessed to having seen neutrons when they weren't there. It was just a mistake of measurements. His tedious work was not all for not, he did come to some conclusions and made steps, however small, towards making it a reality. He had a break through when he used an x ray along with a lead screen. By all laws of physics, the x ray should not have made an emission due to the lead screen but it did. He had his work double checked by a fellow doctor at the University of Russia and he confirmed what Karabut saw but he did not want to be associated with the experiment whatsoever. Dr. Karabut died in March 2015 due to a stroke but his work was continued on by Professor Peter Hagelstein and Dr. Fran Tanzella. 

While majority of experiments have received little to no results, we are still closer to solving the unattainable. Perhaps we will be successful when our great grandchildren have grandchildren but it is a great hope that we succeed.



Resources on cold-fusion: Experimental Evidence - Cold-Fusion IE Magazine Resources on Dr. Alexander Borisovich Karabut: IE Magazine - Karabut Continuing Karabut's experiments - Hagelstein and Tanzella Resources on Pons and Fleischmann: Berkley.EDU - Pons and Fleischmann NY Times - Pons and Fleischmann

Written by Dr. David Alcantara for The All Results Journals