Podcasts about mann whitney

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.18.537143v1?rss=1 Authors: Manolis, D., Hasan, S., Ettelaie, C., Maraveyas, A., O'Brien, D. P., Kessler, B. M., Kramer, H. B., Nikitenko, L. L. Abstract: Background: G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) signalling is implicated in skin-related and cardiovascular diseases, migraine and cancer. However, beyond its agonists and receptor activity-modifying proteins (RAMPs), proteins which bind to CLR and define its properties in primary human cells remain insufficiently understood. Aim: We aimed to profile the CLR interactome in primary human dermal lymphatic endothelial cells (HDLEC), where this GPCR is expressed. Materials and methods: Immunoprecipitation (IP) of core- and terminally-glycosylated CLR from primary in vitro cultured HDLEC was conducted using rabbit polyclonal anti-human CLR serum (with pre-immune serum serving as a control) and confirmed by immunoblotting. Total HDLEC and co-immunoprecipitated CLR proteomes were analysed by label-free quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS). Quantitative in-situ proximity ligation assay (PLA) using ZEISS LSM 710 confocal microscope and ZEN Blue 3.0 and Image J software was performed to confirm LC-MS/MS findings. All experiments were repeated at least three times (biological replicates). For statistical analysis of PLA data, distribution was analysed using Shapiro-Wilk normality test followed by an unpaired t-test or Mann-Whitney test with a p-value of less than or equal to 0.05 interpreted as significant. For MS data of CLR IP samples, statistical analysis was performed using t-test with a permutation-based false discovery rate (FDR)-adjusted p-value of less than or equal to 0.006 interpreted as significant. Results: A total of 4,902 proteins were identified and quantified by LC-MS/MS in primary HDLEC and 46 were co-immunoprecipitated with CLR (p less than 0.006). Direct interaction with the GPCR was confirmed for five of these by PLA (p less than 0.01). Conclusions: This is the first study of its kind to identify novel binding partners of CLR expressed in primary human cells. Our integrative quantitative approach, combining immunoprecipitation of core- and terminally-glycosylated CLR, LC-MS/MS, and PLA, could be applied in a similar fashion to study its interactome in a variety of human cells and tissues, and its contribution to a range of diseases, where the role of this GPCR is implicated. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Factors affecting the choice of statistical test, including level of measurement (nominal, ordinal and interval) and experimental design. When to use the following tests: Spearman's rho, Pearson's r, Wilcoxon, Mann-Whitney, related t-test, unrelated t-test and Chi-Squared test.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.376228v1?rss=1 Authors: Bartha, A., Gyorffy, B. Abstract: Genes showing higher expression in either tumor or metastatic tissues can help in better understanding tumor formation, and can serve as biomarkers of progression or as therapy targets with minimal off-target effects. Our goal was to establish an integrated database using available transcriptome-level datasets and to create a web-platform enabling mining of this database by comparing normal, tumor and metastatic data across all genes in real time. We utilized data generated by either gene arrays or RNA-seq. Gene array data were manually selected from NCBI-GEO. RNA sequencing data was downloaded from the TCGA, TARGET, and GTEx repositories. TCGA and TARGET contain predominantly tumor and metastatic samples from adult and pediatric patients, while GTEx samples are from healthy tissues. Statistical significance was computed using Mann-Whitney or Kruskall-Wallis tests. The entire database contains 56,938 samples including 33,520 samples from 3,180 gene chip-based studies (453 metastatic, 29,376 tumorous and 3,691 normal samples), 11,010 samples from TCGA (394 metastatic, 9,886 tumorous and 730 normal), 1,193 samples from TARGET (1 metastatic, 1,180 tumor, 12 normal) and 11,215 normal samples from GTEx. The most consistently up-regulated genes across multiple tumor types were TOP2A (mean FC=7.8), SPP1 (FC=7.0) and CENPA (FC=6.03) and the most consistently down-regulated gene was ADH1B (mean FC=0.15). Validation of differential expression using equally sized training and test sets confirmed reliability of the database in breast, colon, and lung cancer (p

Welcome back to the Whole View, episode 412. (0:27) Stacy was just talking to Sarah about how discussing covid again is not mentally what she wants to do because she is ready to move past this. In America, covid is not trending in our favor. We do have a couple of questions that we are going to get to, but before we jump into that, Stacy has some exciting, positive news to share. As mentioned previously, Stacy's family has been going through foster training. Early this week, they officially received approval to be resource parents for foster care. It is such a light among all of the darkness 2020 has brought. They started this journey in November 2019. This has been something that has brought Stacy hope and makes her feel like she can make a difference. It is one of those things that Stacy felt called to do, and she is glad she followed her instincts. The process was drawn out because of covid, but they have finally been able to move forward with everything. They hope to welcome some youngsters in need of a safe, stable home in the near future. Stacy will not be sharing anything about the kids moving forward, but she shares this announcement in the hope to inspire others to participate in foster care. It feels as if there is a stigma around fostering, and this is a time in the world where people who live in less than ideal situations are more than ever in need of safe, stable homes. If foster care is something that resonates with you, please look into it as there are so many different ways you can do it to fit your abilities and lifestyle. You are welcome to email Stacy at stacy@realeverything.com and she can share her experience with you and answer questions. Stacy genuinely feels like there is such a need for this right now.   Covid-19 Q & A Series We have a series of questions that will touch at different aspects of covid and our response to it, and our way forward. (5:02) Sarah will also share the latest science available. She hopes that this is a show that answers some of the common lingering questions that have been floating out there. Thank you to everyone who sent questions and for utilizing this show as a trusted resource! They take this role very seriously and put a lot of effort into the research that goes into this show. We hope that you continue to come to us with your questions, and understand that sometimes the answer to your question is 'we don't know'. Sarah wants to start this episode with an email that we received from Cathy. This email encapsulates our experiences in many ways. "Thank you so much for your podcast! Living in Wisconsin where the cases are going up but everything is open my husband and I have chosen to stay isolated. I have not been in a store since March 13, except for two medical appointments and that is it, and I wore a mask for those.  I am 59 years old but feel I am at a higher risk because I am on Humira for RA, have fatty liver disease even though I have never been overweight, have heart and kidney issues both related to birth defects. My diet is AIP, and with a few introductions, I have been in remission for over 2 years.  I have been feeling pretty down the past few days as I had to miss our youngest grandsons 1st birthday party. While I did attend virtually, my adult children and 6 grandchildren are not practicing social distancing, so missing them has been heartbreaking. We do play in the yard together occasionally but maintain our distance. It is so hard not hugging. I do get out for a walk daily, do many crafts so I have been sewing, painting, etc.  I just wanted to thank you for giving the information to continue believing that my husband and I are on the right course."   Stick With It Stacy has such empathy for Cathy. (7:56) We commend Cathy for sticking with it. Stacy knows it is difficult and has been there personally. It is so painful to turn down family gatherings. Stacy is happy to hear that Cathy is getting outside, and engaging as much as she can because this will not end anytime soon. We have to find ways to physical distance. However, we are social beings and our emotional well-being is so dependant on our emotional connection with others. Stacy hopes we can continue to find ways to do this. If you are at risk, it is so hard And while we are grateful for all that technology gives us access to, it still sucks to have to miss out on opportunities. Sarah felt it was important to start this episode with Cathy's comment. It is important to understand how common this experience is. This feeling of stress around being someone who is taking precautions, and feeling like we are missing out, these are real challenges. It is hard to be physically isolated in our homes, and then we have these doubts wondering if we are doing too much. This self-doubt magnifies our feelings of missing out. Sarah wants to emphasize that these feelings are common and it doesn't take away from how important it is to continue to stay at home, social distance, use our mask, and wash our hands. Know that we are together in our aloneness. Help yourself focus on the positives. No matter your circumstances, we can all relate and know that you are not alone.   Germ Exposure Let's start with Jeanie's questions for our Q & A! (16:04) Jeanie writes, "Dear Stacy and Sarah, thank you for your most recent podcast on covid. I know you must be tired of talking about this, but it was so helpful to me, mostly to know that I'm not the only one still concerned about this virus. I live in Missouri where cases are increasing and officials are not taking the virus seriously. Although my hometown of St Louis was mostly following science at the beginning, now that our local cases have fallen, half the population has gone back to life as normal. Like Sarah, I feel so much dismay that science is being disregarded and that this could all be done so much better! I'm so frustrated that we are living in a time where experts are demonized and people make up their own truth, facts, and reality. Masks should not be political, but that is exactly what's going on in Missouri. Except for Trader Joe's, most local stores have too many unmasked individuals, and as Sarah experienced, they do not respect "turns" or personal space. I only have one child, a 10-year-old daughter and she is so lonely from not having any playmates, but like Stacy, my neighbors are not taking the virus seriously enough for her to play with them. It breaks my heart to watch my daughter watch them all play together in the cul-de-sac in front of my house. It will be such a hard decision about whether she will return to school in the fall or be socially isolated indefinitely. A neighborhood mom told me she was going to tell our school board that she won't send back her kids if they require masks--because she believes masks are dangerous to her kids. My Facebook friends that live in the suburban county next to St Louis are posting pictures of their kids at dance competitions, ball games, and swim parties. Even those who were so worried about the virus a month ago! My family is looking around at all this and have begun to question me that we need to be so careful. I was really starting to feel gaslit, especially when we saw the chiropractor. She spent the entire hour trying to convince me that we shouldn't wear masks. I didn't believe most of what she said but I didn't know up from down when I left her office. She really had me questioning myself and my decisions. Your podcast brought me relief and validation.  The chiropractor did say one thing that has been bothering me that Sarah may be able to answer. She says that it's very bad for our immune systems to be socially distancing, that when we all come back together it will be disastrous. I know that historically native tribes have been killed off by the arrival of European diseases they've been isolated from for tens of thousands of years, but are you concerned that you haven't shared any germs with someone outside your family for 3 months? What about if this goes on for a year? Also, I wanted to say that I appreciated the science on how protesters are not spreading the virus and how you have come out in support of Black Lives Matters. It was the right thing to do.  Thank you!"   Being a Parent During a Pandemic Stacy adores Jeanie, and Sarah for not taking any breaths while reading about what the chiropractor told her. (19:17) This has been an issue in Stacy's neighborhood and it is fascinating. Virginia is kind of in the middle. Masks are required legally everywhere in public. This is not being respected by everyone. Matt and Stacy have had to sit down with their kids as a family to discuss this, especially because Matt has the risk of continued exposure. We don't know enough about the virus to know if people could potentially get it twice, and what that impact is. So they have made it clear as a family that they are not returning to life as normal. Stacy was very nervous about going glamping, but they followed certain rules that they set for themselves. They carefully discussed their travel plans and knew the risks, but they did not want to extend that to additional gatherings. It makes it harder to be a parent. Being a parent during this has escalated this to such a higher extent. What will this generation be on the outcome from this all? If you establish what the rules are for you and your family upfront, it makes it that much easier to define what you can and can't do and why. Stacy shared on their experience with birthdays in quarantine, video game virtual socialization, and ways they can connect kids that are not physical. Sarah has been doing the same. All of the topics related to the masks myth that Jeanie referred to in her question were covered in this podcast episode. Please also refer to this post from Sarah on mask use.   Dawn's Question What isolation is doing to our immune systems is something that Sarah wants to address. (27:02) We received a similar question from Dawn, so Sarah wants to read that question and then address both questions together. Dawn says, "wondering if you’re concerned about isolation and how that is affecting all our microbiomes? Gut health has always been so huge for you, so do you have any articles or podcasts on gut immune health related to surviving Covid-19? And do you expect a surge of illnesses related to suppressed immune systems after isolation?" All of this is linked.   Hygiene Hypothesis This ties into the original version of the hygiene hypothesis. (27:38) As originally proposed in the '90s, we needed to have this exposure to pathogens, especially early in life, to help educate and shape the immune system. What has changed about this hypothesis in recent years is the understanding of the gut microbiome. So this entire hypothesis has blended with something called the Old Friends Hypothesis. That actually the thing that we need exposure to is not pathogens, but rather this diverse range of microbial exposure to seed our microbiomes. The Old Friends Hypothesis even recognizes that there are some parasites that our immune systems have coevolved with over millennia. It is not just that we need that exposure, it is that our immune systems actually require the continued presence of these microorganisms in order to fully develop. What we really need is this acquisition of a diverse microbiome and where hygiene has steered us wrong is our overuse of cleaners and disinfectants. This has made our environments so sterile from probiotic organisms, especially environmental probiotics. When we overclean our environments and we are not getting exposed to a diverse species of microbes, this lack of seeding in our microbiomes can result in an overactive immune system. This is one piece of this puzzle. There are a lot of studies showing that social isolation and loneliness can impact immune function. That mechanism is not related to the gut microbiome. The studies show that this is a neuroendocrine mechanism.  We talked about this in TPV Podcast Episode 382: Social Media and see The Health Benefits of Connection. So we do see that social isolation and loneliness can impact immune function. Sarah thinks that the heart of this question is touching on physical isolation's impact on immune function.   Suppressed Immune Systems We have talked about ways we can try to stay socially connected while physically isolated. (31:19) However, there are not many studies about what happens to humans when they live in a sterile environment. This is because there are so few, truly sterile environments in the world. On Earth, there is no such evidence, but the astronauts on the space station do have a suppression of their immune systems. Studies showed that after about 90 days on the space station, especially first-timers, they have about a 50% reduction in the activity of natural killer cell activity. These are a type of cell that go around and find cancer type cells and virally infected cells. They then force these cells to basically commit cell suicide. These are very important cell types for our immune systems, especially in terms of cancer risk and viral infections. For the astronauts, there are three proposed mechanisms: stress, microgravity, radiation (not, lack of infections). The big risk to astronauts, besides cancer, is persistent infections. We are never actually not exposed to pathogens because we carry them with us. There’s no evidence that hermit living on Earth causes immune dysfunction. Although once you re-emerge and have contact with people, you wouldn’t have immunity to viruses that circulated while you were cloistered. So exposure is what would increase the likelihood of infection, not immune suppression. The good thing is that we are currently suppressing the circulation of all those other viruses and bacteria right now. What can we learn to take beyond this pandemic into our normal cold and flu season? If we can physically isolate at the first sign of symptoms, rather than our current societal norm, we could be preventing a lot of regular viral illness, including death from the seasonal flu. By also adopting more of us handwashing as a lifelong habit, we could evolve our norm. Yes, when we get back together there could be some other viruses that we start sharing. However, it is likely to be fairly slow build since we have taken ourselves out of circulation for all of these different viruses.   Gut Health If we are physically isolated, is it impacting our gut microbiomes? (39:34) The most important determinants of the gut microbiome are diet, nutrient status, and hormones, which are a reflection of your lifestyle choices. So these are the most important thing. There is an effective exposure, which we see in studies of family groups. We know that baboons, the closer their relationships are, the more physical interactions they have, the more common their microbiomes are. This is seen in humans too. Married couples who report having a close relationship, will have more similar gut microbiomes to each other than siblings will. This is a reflection of the fact that whenever we touch a person, we are sharing our microbiome. There is potentially an effect if kids are not getting exposed to some bacteria by not being at school. However, this is a very small effect on the gut microbiome compared to the most important thing of a healthy diet, no nutritional deficiencies, and a healthy lifestyle. All and all, Sarah's process for looking after her gut microbiome through physical isolation is no different than at any other time. Work on social connection even with physical isolation. Get Sarah’s new Gut Health Guidebook for optimal diet and lifestyle information. Incorporate probiotics like Just Thrive Probiotic and/or fermented foods And incorporate nature time if you can get is safely. There is no evidence that our immune systems are going to be suppressed by a year of living in our homes. And there is no evidence that our gut microbiomes are going to suffer. The things that are more problematic are the impacts of feeling lonely and socially isolated. This part can suppress our immune systems and can reduce the diversity of our gut microbiome. Stacy and Sarah took a moment to discuss examples that show that no one lives in a sterile environment.   Jessica's Question Jessica's question is a really good follow up to diet and lifestyle is still important. (52:25) She writes, "I know you both said you don't want to do COVID episodes every week buuuutttt, I have a COVID question. I've seen this article passed around along with the general idea that if we pushed real food, metabolic balancing, and immune support, the death toll from COVID would be much lower. In conjunction, there's been criticism of the messaging from media the only pushes vaccines, drugs, and basic immune support. I know this is an oversimplification, but in the spirit of science literacy, I'd love to hear your more nuanced view of why this is or isn't a feasible solution. I'm sure you get lots of questions, but thank you for your science-based approach to whole living! I'm an academic librarian (aka info junkie) recently diagnosed with early-stage Hashimoto's (no medication but high antibodies) so you and Stacy are a god-send!" Stacy thinks that this gets to the root of what we discussed on our last covid show regarding the mixed messaging in the community. Sarah has some science to jump into, but Stacy wants to state that you don't have to pick and choose. Covid can infect anybody in any health situation. Stacy strongly feels that the things we talk about with gut microbiome, sleep, lower stress, healthy eating, and anti-inflammatory lifestyle choices, that this is good for you and your immune system. However, this still doesn't make you immune from covid. There is no diet or healthy lifestyle that would prevent us from getting covid or even guarantee that we wouldn't have a severe course of the disease. We need to figure out a way of communicating healthy choices that don't take away from the messaging around the importance of social distancing, masks, physical isolation, and a safe and effective vaccine. There are so many barriers to adopting a healthy diet and lifestyle, broadly across our entire society, that we faced before this pandemic. It is a multi-dimensional challenge that needs to be overcome.   Nutrition & Covid Risk There is now data showing some nutrient deficiencies are problematic. (1:00:24) Very low selenium intake increases death rate from COVID-19 by 5X. The science behind this can be found here. There is some initial research being done on the impact of supplementation on covid. A combination of B12, D, and magnesium was administered in older COVID-19 patients. This was associated with a significant reduction in the proportion of patients with clinical deterioration requiring oxygen support and/or intensive care support. This is a small preliminary study and has yet to be peer-reviewed. There’s also an ongoing study looking at combo vitamin C and zinc. This is an area of active research with a lot to still learn. However, vitamin D is probably the most relevant nutrient and something that could be incorporated very simply into a national message.   Amanda's Question Amanda writes, "Love all your recent podcasts on covid. (1:02:54) I’m so glad Stacy and her family are doing well. Sarah your research is the topic of many conversations with my family and friends. Recently I read an article talking about a link between low vitamin D levels and covid. Just wondering your thoughts on this. What science have you found to supposition or dispute this if any?" Sarah wants to first provide some context to this question. There is a very well known blogger who came out in early March with an eBook that made a case for avoiding vitamin D supplementation. They said that it increases the ACE2 receptor, which is the receptor that the novel coronavirus is binding to, to enter our cells. Sarah has received a ton of questions on this research. Recently there has actually been a huge increase in studies linking low vitamin D levels with an increase in severity of covid. The first few studies were done at the population level, which means it was hard to identify cause and effect. So they were correlating country/territory latitude or average vitamin D deficiency rates with mortality rate, varying results, from null to double mortality rate. The results were varied, which you can read more about here. Now, there are studies where individuals have vitamin D levels measured. It is showing that there is quite a large effect.   Vitamin D & Covid-19 There have been quite a few studies that have looked at this. (1:05:38) One analysis that is just being published now, shows that this might be as much as a factor of 2. So having an adequate vitamin D status halves the mortality rate, compared to having vitamin D deficiency. There have been studies that have actually looked at vitamin D deficiency versus insufficiency. Backman said, "It will not prevent a patient from contracting the virus, but it may reduce complications and prevent death in those who are infected." For more on this, see here and here. Testing positive for COVID-19 was associated with increasing age and being likely vitamin D deficient, as compared to likely vitamin D sufficient.  Sarah shared the data from this study. Please also refer to this study and this study for more information on the statistical analysis that was carried out using Mann-Whitney. When you look at this collection of studies, it has just in the last month become really clear that low vitamin D is a risk for severe covid and death. Even these studies are suggesting these really high-level doses of vitamin D to address this prevalent deficiency. There have been some studies showing that perhaps one of the reasons why the rates have been lower in the northern hemisphere in the summer is related to the fact that when people are outside their vitamin D levels go up.   The ACE2 Receptor ACE2 is an enzyme that is membrane-bound.  (1:10:46) When a respiratory droplet containing SARS-CoV-2 enters your mouth or nose, it’s easily inhaled into your airway where it encounters pulmonary cells that have ACE2 enzymes embedded within their surface membranes. ACE2 is a type I transmembrane metallocarboxypeptidase that degrades angiotensin-2, thereby negatively regulating the renin-angiotensin system to lower blood pressure. ACE2’s role in regulating blood pressure is why hypertension is such a major risk factor for a more severe course of covid-19 illness. It is also found in arteries, heart, kidney, and intestines. The now infamous spike proteins on the outside of SARS-CoV-2 bind with ACE2, releasing the fusion machinery that the virus uses to dump its RNA and viral proteins into the target cell, where it hijacks the cells organelles to produce viral replicas instead of all of the various proteins that the cell needs to survive. It’s true that vitamin D increases ACE2 in various models of pulmonary injury, hypertension (see here and here). So the simplistic view spreading across the internet is to reduce ACE2 with vitamin d deficiency and you can’t get infected. WRONG!  Not only is vitamin D critical for the immune function to help fight off the virus BUT increasing ACE2 in covid is a REALLY GOOD THING! The truth is the complete opposite. It is very very important to test vitamin D levels, and supplement to bring your levels up to normal. Researchers are suggesting at least 60 nanograms per milliliter as a target. This is a discussion to have with your doctor. The whole argument of avoiding vitamin D because it increases ACE2 is completely backward. You are not going to reduce ACE2 with vitamin D deficiency to a point where the virus can't get in. It can get in no matter what. Covid-19 normalizing ACE2 levels in the context of lung injury is very very beneficial. For more information on this, be sure to also reference this article and this one and this one. This is a reminder about the importance of making sure your information is correct before putting it out into the world.   Covid-19 & Minority Groups There have been some comments online that the reason why the Black community has been so much more affected by covid is that they have a higher likelihood of being vitamin D insufficient. (1:20:50) This is due to the higher levels of melanin in their skin. You can read about this here. In this study, sex and ethnicity differential pattern of COVID-19 was not adequately explained by variations in cardiometabolic factors, 25(OH)-vitamin D levels or socio-economic factors.   Mary's Question Mary asks, "I have a question about covid19. (1:22:55)  I was sick March 9-29 with fever and other wonderful symptoms! Doc told me I probably had covid19. Thankfully I wasn’t sick enough to be hospitalized  (or tested here in GA) and I’m finally feeling much better. Still tired and having more RA pain but trying to ease AIP with reintros! Hubby and I (both 62 yrs old) got tested for the antibodies, and we’ve both tested positive. Everything on the web is saying they don’t know if that means we’re immune to the disease or can get it again. My in-laws (95&94) live in KY and we’d love to go see them and the rest of the fam. Should we just continue to live our face masked life (we still wear them inside the grocery in consideration of others) and not visit? We are interacting with a small group of neighbors in the hood, playing pickleball, but washing hands and wiping down paddles and balls, etc... no hugging, no high fiving, somewhat social distancing (not perfect). We don’t know anybody else that has had covid19 or had symptoms. Wondering if you’ve found any research concerning immunity and contagion if immune?"   Immunity The science part of this question is that we don't really have a good sense for how long you might be able to shed virus after your symptoms go away. (1:25:35) There is some research showing that people can shed virus for at least 24-days, and more public health officials are trying to talk about this. The suggested 14-day quarantine period is likely insufficient. Based on what officials are recommending, you should quarantine for 14-days after symptoms end. Even that might not be enough. There have been cases where people have tested positive for months. Some of these people have been sick for this whole period of time, and this is another thing that we don't yet understand. We don't know how long you are contagious for, and we don't know how long immunity lasts. This piece of the question is unfortunately something we can't answer at this time. We don't know if having antibodies (or what level of antibodies) is enough to protect you from reintroduction. And we don't how long after your symptoms end before you are no risk to the people around you. This makes making a decision on how to handle life post covid really hard to navigate. Stacy thinks the hardest part for them was sending Matt back to work. As Matt and Stacy returned to life after they were sick, they did have to have dialogues with people about how they were handling things given the unknown. Communication is essential. Matt and Stacy did their best to clean their house after they were sick, but it is not a personal skill of Stacy's. More than 30-days after Matt and Stacy were symptom-free, they decided to ask their long-time house cleaner to return after having a conversation with her to determine her comfort level with returning. If you have had the virus, there is no stigma with it, but you need to let people know. It is only fair that others know your information so that they can be careful. Stacy's takeaways after being sick were to quarantine for as long as possible and to communicate with people. Sarah applauds Mary for still wearing a mask to both be considerate and be a role model.   Closing Thoughts It has been a doozy of a show! Stacy and Sarah want to thank all of our listeners for submitting questions. And a huge thank you to Sarah for pulling all of the science together. As mentioned last week, we do have something coming for you in the very near future. Make sure to stay tuned, join our email lists, and we will be connecting with you more on this very shortly. We will be back again next week. Thank you again for listening, we know this was a long show. We appreciate those who have stuck with us! (1:38:25)

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview again features Dr. David Baker, Professor of Neuroimmunology at Queen Mary University of London in the U.K. We spoke at the ECTRIMS conference last fall. In part one of our interview he raised the issue of why there has been very poor translation from animal models to clinical trials. Today, Dr. Baker, also known as the ”Mouse Doctor” for his work with animal models, lays out why this situation exists and what to do about it.   Interviewee – David Baker I think there’s many reasons why, and I think we all have our failings. And one can point the finger at the animal models, which a lot of the clinicians do, saying it’s the animal model’s fault, which is possible. But I think also we have to look at humans and how humans use their animal models. And then how humans translate the data from the animal models into the clinic, because I think there’s many failings along the line, and I think that’s one of the reasons for the failing between the two.   I think one of the failings is, in terms of the animal models, that when we do our animal models for these, we’re looking for mechanisms not treatments. And so about 70% of studies give drug before disease is ever induced, which never happens in a human. You know, you go after you’ve had one or two or more attacks before you’re given drugs. We also use the drugs in a way that are never used in a human, so people will do what they call a prophylactic drug where they’ll give it before the disease manifests itself. Or a therapeutic dose, which is probably when the animals are showing their symptoms. But in reality, a human would be getting steroids at that time point. They would never get a DMT. So you’re not comparing, you know, apples with apples. You’re comparing apples with pears, and I think that’s one of the problems.   And I think, you know, if you try and block an immune response from being generated, that’s quite easy compared to stopping an immune response once it’s been generated, because immunity’s about giving life-long protection against infections. And so I think it’s a different type of beast to target. So I think this is where the animal models could do it, because EAE is one of the few where you have this relapsing-remitting disease course. But it’s very, very rare that people actually start to treat in between attacks to block further relapses. I think that’s one of the problems.   The other big problem is the dose; the dose relationship between animals and humans. There’s a tendency we just keep giving more and more and more and more, and eventually the drugs will work. But you’ve got this problem that animals are very liable to be stressed, and we call it the building site effect, so construction site effect. And if you have lots of loud noises, it scares animals. They get very stressed, and your EAE just disappears. And likewise, if you just give lots and lots of drug, that probably tastes nasty. They get stressed out as well. And I think many of the so-called wonder cures – cures of the week – are because we’re just giving too much, which doesn’t have a relationship to what the human dose is going to be.   And then, likewise, I think we’ve got too much of a publication bias for the need to generate positive data. And I think what we then have to do is we have to look at the quality of the data. And I think there has been a lot of failure to replicate data. I think some of that is because some studies lack quality control, and the way I look at that – and I could be wrong; obviously it’s an opinion – but if you look at the way that EAE is scored (it’s normally a scoring system 1 to 3 or 1 to 4) and then you have your drug, which may be, you know, takes your control down from 3 down to a 1. But then, every now again, you look at the studies where it goes either way, and your controls are at 1 and it goes up to 3, and I ask the question how do you get a score of 1? Because if you had four animals, they’re all scoring 1. Or is it three animals score 0 and one score 4, and that will give you a score of 1. And I think if people were made to actually put the data about how many animals got disease, we’d be able to interpret those line graphs. Because I feel that, in many cases, some of those graphs lack quality control.   If you have a robust quality control system, your control group should be giving you roughly the same type of scores every time. But in individual papers you can see, in some groups you have a score of 1 in the control group. The next experiment it’s a score of 3. To my mind I think if you look at that, then those are probably the experiments are much more likely not to replicate. So I think you have to be, obviously, skeptical, but I really would like people to actually probably give us the information about how many animals got disease – what is their mean score – in addition to those line graphs. Because without that, they’re impossible to interpret.   So that’s, you know, kind of one problem of the animals. And then for the humans, you have the same problems. So they over-interpret the animal data. The people doing the clinical trials are very, very rarely the people who came up with the idea. So if there’s a weird side effect that you may know about, you know, that’s not translated to the person who’s actually doing the study, because they don’t talk to the basic scientists. Then they probably underpower the studies. They don’t necessarily pick the right outcome measurements. So I think there’s many failings in both sides of the equation, and it’s not always the animal model. But I think unless we kind of up our game, I think it’s going to be very difficult for the people who are working on animal models, because you know, there are treatments that come along for, you know, the immune part of multiple sclerosis.   And if you’re thinking about the ethical use of animals, it’s much harder to make the ethical argument that you should be using disease models which are very severe for the animals to try and work out fundamental parts of biology. And, therefore, I think we’ll find that you know the funding agencies start to say, well, why are we funding this work? So I think we need to have good quality work, because if we don’t have good quality work, it allows that clinical view that animal work doesn’t really deliver the treatments. And I think they can deliver the treatments, but we just have to use our animal studies wisely to ask questions rather than, you know, blindly saying this will work in multiple sclerosis because it works in EAE. That doesn’t make sense to me.   Interviewer – Dan Keller Do you have any succinct tips for people who are either reviewing papers on animal studies or people who are reading those papers once they’re published or even the general public reading a news story?   Dr. Baker Well my first tip would be probably – and this is okay as an opinion – but, you know, EAE data is nonparametric. It goes 1, 2, 3, 4; it’s not a continuous scale, so first tip is don’t use, you know, the t-test of parametric data on nonparametric data. And that does make a difference. There is a Nature paper published this year that was analyzed with a t-test. If you analyze it with a Mann-Whitney test, which you should have done, the data becomes nonsignificant. So rather than the take home message is, you know, this is a new wonder drug for multiple sclerosis, their answer should have been you have to go back and reproduce your EAE experiment because it didn’t work. So I think that would be the first tip. And then the second tip, I would really like people to say, tell us how many animals get disease and on what level and when, so we can interpret the line graph.   MSDF This is something that you routinely see in oncology done right. They talk about percent of responders, and among responders, what was the shrinkage of the tumor? They don’t average it out among all the people who dilute it out by not responding.   Dr. Baker Well I think one of the problems as well is we’ve also got this publication bias. We’ve got you know this urge to see positive data, and I think that skews the whole system.   MSDF Has anything changed since you came out with a response to the animal checklist?   Dr. Baker I think, sadly, no, but we’re actually doing the checklist again, so we will be able to see if things have changed. I don’t think it has. I think the message hasn’t gotten through. But I think – this is, again, another one of those nails in the animal model coffin that, if we don’t up our game, we’ll be seen to be doing an inferior quality work and eventually we’ll get discarded. So I know that some of the grant councils are, as you know, saying this is a condition of your grant. But I think you know it’s been slow to change, and I think one of the reasons is actually people who are leaders of the field actually are some of the people who are some of the worst offenders. So we’re leading by bad example rather than good example.   MSDF We don’t want to leave the listener with the impression that you’re against animal models. I mean, you’re known as “Dr. Mouse,” so you know I guess you just want to see them done well.   Dr. Baker Yes, I’m passionate. I mean, I really you know believe animal models have a real positive impact to do. And I’ve been really lucky in the recent years is that, you know, some of those animal models – and work we’ve done from animal models – is going through into humans and you know is starting to make the difference. So you know our work with the Cannabis was great. You know, it shows that you know our animal work has validity. Without the animal model stuff we’ll never really understand the biology. You can’t do all the experiments in humans. You do need experimental systems to be able to ask questions. And you need to be able to invent.   And you know there is some fantastic work. You know I’ve picked up the papers, and I get really excited by it, but I think, at the same time, we have to also be a drum to say, you know, try and improve the quality. Because, at the end of the day, it’s more likely that if you’re doing good quality animal experiments, that other people will be able to replicate it. And it will move the field on further and faster. And I think if people believe what we produce as being good solid work, then it’s going to be a win-win situation.   MSDF It would be nice to see sort of a meta-analysis of animal studies that are considered to have been done well versus those not and see which ones translated into advances in the human situation, because so many times they say, well, sure it works in animals, but it doesn’t work in humans. Well if it works in animals because it was set up not so well, then that might be a reason not to work in humans.   Dr. Baker Yes. I think you know the problem of animal models has got nothing peculiar to the multiple sclerosis field. It’s just a common theme. And I think that tells me it’s not a problem of animal models, because if it’s so common in every other discipline, it tells us it’s something how we use the animals is the fundamental problem. Now, you know for MS, we don’t really know. I mean, I think this going to be the – we’re at ECTRIMS now, and I think the whole world can change a little bit today, or in the next few days, because we’ve always thought of MS as being a T cell-mediated disease. Now that may be still the true answer, but now we’re starting to see ocrelizumab, which is a big B cell depleting antibody probably – I’m predicting – to have as good an effect as anything that the T cell you know brigade has ever done. And, in fact, if you look at most of the MS drugs, you would say that most of them actually are inhibiting B cell function.   Now, does that tell us that B cells are driving the disease? It may well do. Or it may well not. Now some people could argue – and they will – you know they’re the reservoir for the virus that causes multiple sclerosis. And then other people will say, well, actually the antigen-presenting cells. And let’s see, but I think what we’ll find is you know EAE will have to have changed its focus. We’ve been focusing our studies on T cell biology, but in fact, the T cell-inhibitory molecules haven’t really delivered. So is that right? And it may well be you know we have to think of a different biology. But EAE can certainly do that if need be.   So we’ll have to you know try and work out how do these B cell-depleting agents work. Is it you know via antigen presentation or not? I don’t know.   MSDF We’ve always thought of T cells as regulating B cells. Now it looks like they both regulate each other.   Dr. Baker I mean, I have my history in skin diseases, and when I first started working, actually my boss was more interested in B-regulatory cells. T-regulatory cells kind of hadn’t really existed at that time point. So I think we’re trying to reinvent the wheel. If we look throughout the literature, it’s a cross-talk between T and B cells are probably the answer. And we’ll see. Again, from our animal studies, we’ve had animal studies where we’ve manipulated the immune system making sure that has a positive effect. We’ve been able to translate that, so we have an N of 1 where we’ve got rid of somebody’s neutralizing beta-interferon antibodies by antigen-specific mechanisms. Now if we could translate that into MS, then we may have a way of treating MS. But we’ll see.   MSDF Very good, thank you. I appreciate it.   Dr. Baker Okay.   [transition music]   MSDF Thank you for listening to Episode Ninety-eight of Multiple Sclerosis Discovery. This episode is the final one in our series of MS podcasts. We hope that the series has been enlightening and has spurred further discussion about the causes of MS and related conditions, their pathological mechanisms, potential ways to intervene, and new research directions. We’ve tried to communicate this information in a way that builds bridges among different disciplines, with a goal of opening new routes toward significant clinical advances. Although we won’t be adding any new podcasts, the series will remain available on the MS Discovery website for the foreseeable future.   This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.   [outro music]   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   For Multiple Sclerosis Discovery, I'm Dan Keller.

Background: The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, beta-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types. Methods: A retrospective analysis was performed on the expression of MUC1, beta-catenin and E-cadherin by immunohistochemistry on tumor tissues of a series of 112 breast cancer patients (total collective) treated in Munich between 2000 and 2002. By matched-pair analysis, 46 patients were entered into two comparable groups of 23 patients after categorizing them as having multicentric/multifocal or unifocal breast cancer. Matching criteria were tumor size, histology grade and lymph node status; based on these criteria, patients were distributed equally between the two groups (p = 1.000 each). Data were analyzed with the Kruskal-Wallis and the Mann-Whitney tests. Results: In the matched groups, we found a significantly down-regulated expression of E-cadherin in multicentric/multifocal breast cancer compared to unifocal disease (p = 0.024). The total collective showed even higher significance with a value of p < 0.0001. In contrast, no significant differences were observed in the expression of beta-catenin between multicentric/multifocal and unifocal tumors (p = 0.636 and p = 0.914, respectively). When comparing the expression of MUC1, E-cadherin and beta-catenin within the unifocal group, we found a significant positive correlation between E-cadherin and beta-catenin (p = 0.003). In the multicentric/multifocal group we observed, in contrast to the unifocal group, a significant decrease of MUC1 expression with increased grading (p = 0.027). Conclusion: This study demonstrates that multicentric/multifocal and unifocal breast cancers with identical TNM-staging clearly differ in the expression level of E-cadherin. We suggest that the down-regulation of E-cadherin in multicentric/multifocal breast cancer is causally connected with the worse prognosis of this tumor type.

Background Poor platelet inhibition by aspirin or clopidogrel has been associated with adverse outcomes in patients with cardiovascular diseases. A reliable and facile assay to measure platelet inhibition after treatment with aspirin and a P2Y12 antagonist is lacking. Multiple electrode aggregometry (MEA), which is being increasingly used in clinical studies, is sensitive to platelet inhibition by aspirin and clopidogrel, but a critical evaluation of MEA monitoring of dual anti-platelet therapy with aspirin and P2Y12 antagonists is missing. Design and Methods By performing in vitro and ex vivo experiments, we evaluated in healthy subjects the feasibility of using MEA to monitor platelet inhibition of P2Y12 antagonists (clopidogrel in vivo, cangrelor in vitro) and aspirin (100 mg per day in vivo, and 1 mM or 5.4 mM in vitro) alone, and in combination. Statistical analyses were performed by the Mann-Whitney rank sum test, student' t-test, analysis of variance followed by the Holm-Sidak test, where appropriate. Results ADP-induced platelet aggregation in hirudin-anticoagulated blood was inhibited by 99.3 ± 1.4% by in vitro addition of cangrelor (100 nM; p < 0.001) and by 64 ± 35% by oral clopidogrel (600 mg) intake (p < 0.05; values are means ± SD). Pre-incubation of blood with aspirin (1 mM) or oral aspirin intake (100 mg/day for 1 week) inhibited arachidonic acid (AA)-stimulated aggregation >95% and 100 ± 3.2%, respectively (p < 0.01). Aspirin did not influence ADP-induced platelet aggregation, either in vitro or ex vivo. Oral intake of clopidogrel did not significantly reduce AA-induced aggregation, but P2Y12 blockade by cangrelor (100 nM) in vitro diminished AA-stimulated aggregation by 53 ± 26% (p < 0.01). A feasibility study in healthy volunteers showed that dual anti-platelet drug intake (aspirin and clopidogrel) could be selectively monitored by MEA. Conclusions Selective platelet inhibition by aspirin and P2Y12 antagonists alone and in combination can be rapidly measured by MEA. We suggest that dual anti-platelet therapy with these two types of anti-platelet drugs can be optimized individually by measuring platelet responsiveness to ADP and AA with MEA before and after drug intake.

Nach 12-monatiger Einnahme einer hochaktiven antiretroviralen Therapie (HAART) kommt es in ca. 45% der Fälle zum Auftreten des HAART-assoziierten Lipodystrophiesyndroms (LDS) (23). Das LDS beinhaltet u.a. Dyslipoproteinämien mit Gesamtcholesterinwerten von oftmals >300 mg/dl. Am häufigsten werden sie unter einer HAART beobachtet, die Proteaseinhibitoren (PI) beinhalten. Die Hypercholesterinämie gilt als etablierter Risikofaktor für die Entstehung einer Atherosklerose. Gegenstand der aktuellen wissenschaftlichen Diskussion ist die Frage, ob auch die HAART-induzierte Hypercholesterinämie atherogen wirkt. Mehrere Fallberichte und prospektive Studien über kardiovaskuläre Ereignisse bei HIV-infizierten Patienten unter HAART sind bereits veröffentlicht. Ein direkter Nachweis atherosklerotischer Schädigungen der Koronarien erfolgte bisher jedoch nicht. In der vorliegenden Arbeit wurde untersucht, ob eine HAART-induzierte Hypercholesterinämie zu morphologischen und funktionellen Veränderungen an den Herzkranzgefäßen führt. 1.1. Patienten und Methoden Patienten: Gruppe A umfasste 20 HIV-infizierte Patienten mit PI-haltiger HAART und HAART-induzierter Hypercholesterinämie >300mg/dl seit mindestens 24 Monaten. 17/20 Patienten wurden auf morphologische und 12/20 Patienten wurden initial und 5/20 nach 12 Monaten noch einmal auf funktionelle Veränderungen der Koronarien untersucht. Die Kontrollgruppe B umfasste 8 HIV-infizierte Patienten ohne HAART mit Gesamtcholesterinwerten 0,05), wohl aber nach Adenosinbelastung signifikant niedriger als bei Gruppe B (66±17 versus 35±11, p0,05). Nach Adenosinbelastung stieg die Myokarddurchblutung aber signifikant weniger stark an als in Gruppe B (1,58±0,44 versus 2,93±0,68, p

Fragestellung: Die klinische Herz-Xenotransplantation scheint aufgrund vielfältiger wissenschaftlicher Fort-schritte wahrscheinlicher zu werden, jedoch könnten präformierte natürliche Antikörper, die ohne vorausgegangene Sensibilisierung im Blut vorhanden sind und Antigene fremder Spezies erkennen, auch bei therapeutischer Bewältigung der initialen hyperakuten Abstoßungsreaktion zur anhaltenden Transplantatdysfunktion führen. Tage bis Wochen nach Antigenerstkontakt käme es im xenogenen System zusätzlich zur Bildung induzierter Antikörper, die gegen das Fremdgewebe gerichtet sind. Ziel der vorliegenden Arbeit ist, an spontan kontrahierenden Kardiomyozyten das Wirkungs-profil präformierter natürlicher Antikörpern im Vergleich mit induzierten Antikörpern (durch Verimpfung von Rattenherzgewebe oder Rattenherzzellen in Kaninchen gewonnen) zu unter-suchen. Methodik: Zu Kulturen spontan kontrahierender, neonataler Rattenkardiomyozyten werden Seren zuge-geben, die präformierte oder induzierte Antikörper enthalten (dialysierte, Elektrolyt-, pH-, thermoäquilibrierte, mit Medium verdünnte Seren). Im Vergleich zu den nativen Seren wer-den dieselben Seren nach Entfernung der xenoreaktiven Antikörper aus den Seren (messbar durch den Hämagglutinationstiter gegen Rattenerythrozyten) und/oder Inaktivierung der Komplementkomponenten untersucht. Zum Einsatz kommt einerseits humanes Serum mit ei-nem hohen Gehalt an präformierten xenoreaktiven Antikörpern; Spenderserum wird hierbei im Vergleich mit kommerziell erhältlichen Humanimmunglobulinpräparationen eingesetzt. Andererseits wird Serum mit einem hohen Gehalt an spezifischen induzierten Antikörpern gegen Rattenherzepitope in den Inkubationsexperimenten verwandt. Das Serum wurde nach Verimpfung von Rattenherzgewebe oder Rattenherzzellen in Kaninchen gewonnen. Die Kontraktionen werden über ein Phasenkontrastmikroskop mittels eines photoelektrischen Systems registriert und videotechnisch dokumentiert. Als Parameter der Kontraktilität dienen die Frequenz, Amplitude und Kontraktions-/Relaxationsgeschwindigkeit. Das Ausmaß der synzytialen Kopplung im Zellverband wird als Streuung der Kontraktionsfrequenzen (Variati-onskoeffizienten, Tests nach Hartley, Mann-Whitney und Cochran, Scatterdiagramme) ermit-telt. Als Zytotoxizitätsparameter werden der zelluläre Gehalt an Kalium und Protein sowie an energiereichen Phosphaten, die Trypanblauaufnahme und die elektronenmikroskopisch er-fassbare Ultrastruktur bestimmt. Der Nitritgehalt des Kulturüberstands als Endprodukt des Stickoxidmetabolismus fungiert als ein Maß für die Zellaktivierung. Ergebnisse: (1) Spontane Zellkontraktionen neonataler Rattenkardiomyozyten kommen nach Gabe von Seren mit präformierten natürlichen Antikörpern - einem stereotypen, reproduzierbaren Mus-ter eines geänderten Schlagverhaltens folgend - zu einem passageren Stillstand, der über eini-ge Minuten anhält und spontan reversibel ist. Die Kontraktionen bleiben anschließend über Stunden desynchronisiert in Gegenwart der präformierten natürlichen Antikörper im Sinne einer Entkopplung des funktionellen Synzytiums der Zellmonolayer; dabei bleiben die Kardi-omyozyten vital, jedoch kommt es zu einer Zellaktivierung, kenntlich an einer vermehrter zel-lulären Nitritproduktion. Absorption der spezifisch gegen Rattenepitope gerichteten xenoreak-tiven Antikörper, nicht aber Dekomplementierung der Seren verhindert die Desynchronisati-on. (2) Seren mit induzierten Antikörpern führen dagegen zeit- und konzentrationsabhängig zur Zytotoxizität bis zum Zelltod der neonatalen Rattenkardiomyozyten. Hierfür sind sowohl Komplementkomponenten als auch induzierte xenoreaktive Antikörper erforderlich. Schlussfolgerungen: Präformierte natürliche Antikörper könnten in vivo eine Dysfunktion xenogener Herztrans-plantate im Sinne einer fehlenden synzytialen Koordination der Kardiomyozyten auslösen. Induzierte Antikörper haben eine zytotoxische Wirkung, die die Zellintegrität gefährdet.

In einem prospektiven, hypothesengeleiteten Design mit zwei Messzeitpunkten wurde die Krankheitsverarbeitung (Bewältigungsstrategien, Kausal- und Kontrollattributionen) von Patienten mit malignen Lymphomen sowie deren Zusammenhänge mit Lebensqualität und emotionalem Befinden vor und sechs Monate nach Hochdosischemotherapie mit autologer Blutstammzelltransplantation untersucht. Neben soziodemographischen Daten wurden medizinische Parameter wie Karnofsky-Index und Remissionsstatus erhoben. Die Untersuchung stützte sich auf multidimensionale, standardisierte und normierte Testverfahren, deren Gütekriterien an verschiedenen Stichproben, großteils auch an Krebspatienten, überprüft worden waren. Im Erhebungszeitraum (März 1999 bis August 2001) konnte eine Stichprobe von n=69 Patienten akquiriert werden. Diese reduzierte sich aus Gründen von Tod, anderer medizinischer Behandlung und persönlicher Ablehnung auf n=45 zum zweiten Erhebungszeitpunkt. Im Hinblick auf soziodemographische und medizinische Parameter wurden die Patienten mit der Studie von Langenmayer, 1999 an autolog blutstammzelltransplantierten Lymphompatienten und mit Daten der Normalbevölkerung (Statistisches Bundesamt Wiesbaden) verglichen. Die statistische Auswertung erfolgte in Abhängigkeit vom Skalenniveau und den Verteilungscharakteristika der Daten mit Hilfe von parametrischen und nonparametrischen Verfahren. Neben t-Test-Vergleichen, dem U-Test nach Mann-Whitney und Wilcoxon, den χ2-Techniken, der Produkt-Moment-Korrelation nach Bravais-Pearson und Spearman’s Rangkorrelation, wurden ein- und mehrfaktorielle Varianzanalysen, multiple Regressionsanalysen und Clusteranalysen nach der Ward-Methode berechnet. Um Scheinsignifkanzen durch α-Fehler-Kumulierung zu vermeiden, wurden die Irrtumswahrscheinlichen nach der Bonferroni-Methode korrigiert. In der Krankheitsbewältigung (FKV) zeigte sich eine im Vergleich mit Muthny et al., 1992 geringere Tendenz zum sozialen Abwärtsvergleich, was möglicherweise mit der Schwere und Lebensbedrohlichkeit der Erkrankung in Zusammenhang steht. Bei den subjektiven Kausalattributionen (PUK) konnten im Hinblick auf Lebensqualität und emotionales Befinden adaptive und maladaptive Formen identifiziert werden. Dies spricht gegen die prinzipielle Maladaptivität subjektiver Krankheitstheorien (Riehl-Emde et al., 1989; Muthny et al., 1992; Faller et al., 1995). Die Attribution auf "Umweltverschmutzung" ist bei Krebspatienten häufig (vgl. Becker, 1984; Verres, 1986) und erwies sich als adaptiv; "Gesundheitsverhalten", "Alltagsstress", "Verarbeitungsdefizite", "eigene seelische Probleme" und "geringes Durchsetzungsvermögen" hingegen als maladaptiv. Der Autor vermutet Zusammenhänge mit Selbstbeschuldigungsprozessen, was durch eine multivariate Varianzanalyse gestützt wurde: die bislang noch nicht publizierte Differenzierung zwischen natur- und handlungskausalen Attributionen erwies sich als einzig signifikanter Einflussfaktor auf Lebensqualität und emotionales Befinden im multivariaten Vergleich. Naturkausal werden solche Attributionen bezeichnet, auf die der Patient intentional keinen Einfluss nehmen konnte (z.B. Zufall, Schicksal, Vererbung), während handlungskausale Ursachen prinzipiell veränderbar gewesen wären (z.B. hohe Anforderungen an sich selbst, Alttagsstress, berufliche Belastungen). Patienten mit handlungskausalen Attributionsmodellen hatten eine signifikant geringere Lebensqualität, geringere emotionale Funktion und erhöhte Werte an affektiven Belastungen: sie waren häufiger niedergeschlagen, müde und missmutig; auch gaben sie signifikant mehr Ursachen für ihre Erkrankung an, zudem in höherer Gewichtung. Es zeigte sich ein positiver Einfluss internaler Kontrollattributionen auf Lebensqualität und Rollenfunktion sechs Monate nach autologer Stammzelltransplantation, was die Untersuchungen von Baider & Sarell, 1983; Reynaert et al., 1995 und Eckhardt-Henn et al., 1997 bestätigt, unserer Hypothese aber widerspricht, dass sich im Setting der Hochdosischemotherapie mit Angewiesenheit auf Ärzte, Pflegepersonal und Angehörige sozial-externale Attributionen als adaptiver erweisen würden. Hinsichtlich des Remissionsstatus und einiger soziodemographischer Parameter ergaben sich geringe bis mittelstarke Zusammenhänge mit der Krankheitsbewältigung, Kausal- und Kontrollüberzeugungen. Diese hielten einer Bonferroni-Korrektur jedoch nicht stand, so dass sie lediglich als Tendenzen interpretiert werden dürfen. Keine Zusammenhänge zeigten sich in Bezug auf den Karnofsky-Index und die Diagnosegruppen. Mit Clusteranalysen nach der Ward-Methode wurden die untersuchten Patienten eindeutig differenzierbaren Clustern der Krankheitsbewältigung (FKV) bzw. Kontrollattribution (KKG) zugeordnet. Letztere entsprachen den von Wallston & Wallston, 1982 beschriebenen "rein internalen" bzw. "doppelt externalen" Typen, dem des "Nay-sayer" und "Type thought not to exist". Es zeigten sich wenig signifikante Unterschiede im Hinblick auf Lebensqualität oder emotionale Belastungen. Die Zusammenhänge zwischen emotionalem Befinden und Krankheitsverarbeitung wurden mit kreuzvalidierten, multiplen Regressionsanalysen untersucht. Dabei leistete der Autoregressor jeweils einen wesentlichen Beitrag zur Varianzaufklärung des Kriteriums. Insgesamt scheinen die Bewältigungsstrategien das emotionale Befinden vorwiegend in den distalen Modellen zu beeinflussen, während in den proximalen Modellen auch Einflüsse des Karnofsky-Indexes bestehen. Da sich in der vorliegenden Untersuchung wie auch bei Filipp et al., 1989 und Faller et al., 1994b die Zusammenhänge für die verschiedenen Kriterien und Prädiktoren unterschiedlich darstellten, sollten kausale Beziehungen zwischen Coping und Befinden für jede Krankheitsverarbeitungsform bzw. jedes Adaptationskriterium separat überprüft werden. Die Verarbeitungsmechanismen erwiesen sich im matched-pair-Vergleich als relativ änderungsinvariant im untersuchten Sechs-Monatszeitraum. Dies widerspricht der These von Faller, 1988, nach der es sich bei subjektiven Krankheitstheorien um situationsabhängige Argumentationsprozesse handelt, wie auch der von Lohaus, 1992 beschriebenen Variabilität von Kontrollüberzeugungen. Die Krankheitsverarbeitung könnte mit Persönlichkeitsmerkmalen in Verbindung stehen, was künftige Studien untersuchen sollten. Möglicherweise kann die Unterscheidung zwischen natur- und handlungskausalen Attributionen künftig sowohl bei der Skalierung als auch bei der Identifikation einer Risikogruppe von Patienten behilflich sein, die einer besonderen psychotherapeutischen Unterstützung bedürfen.

In the present experimental essay the effect of controlled ventilation with the UNO Micro-Ventilator? (UMV) on the mouse is examined. The UMV is a pressure controlled and volume limited ventilation device with a sinus ventilation pattern and lowflow rebreathing of the respiration gas. Not only the impact of a preoxygenation is assessed but also the effect of different respiratory rates on mice of different weight. The assessment is made with blood gas analysis, circulatory parameters and histological examinations of the lungs. The animals can be assigned to nine groups: The non-preoxygenized animals are split up in six groups and the preoxygenized ones in two groups. Additionally, group H serves as histological control group. The non-preoxygenized animals of N100 are ventilated with a respiratory rate of 100 /min (n = 6), i.e. the animals of the N130 with 130 /min (n = 6). The animals in N100L (n = 8 settings) are non-preoxygenized, weigh between 25 and 38 grams and the respiratory rate is adjusted to 100 /min. The animals of the group N100S (n = 7) which weigh between 39 and 50 grams are not preoxygenized either. In P80L (n = 7, settings) the animals are ventilated with 80 /min, are preoxygenized, and their weight varies between 25 and 38 grams. Grouped in P80S (n = 7) are animals which weigh between 39 and 50 grams. Group H (n = 7, animals) was not ventilated and serves for the histological examination. To expose the animals to as little stress as possible they are premedicated to the intubation with the completely antagonizable injectable anesthesia medetomidine, midazolam, and fentanyl (MMF). With the beginning of the anesthesia with isoflurane (the concentration of the isoflurane is 2.7 vol.-%) the injectable anesthesia is antagonized with atipamezol, flumazenil, naloxone (AFN). The anesthesia lasts 100 minutes. The A. carotis of all ventilated animals is canulated in order to measure the blood pressure and take blood samples. Besides the blood gas results (pHa, pa CO2, paO2, BE, HCO3¯) the measured parameters are the blood pressure (in mmHg) and the heart rate (in beats /min). To ascertain the normal distribution the Kolmogorov-Smirnov test is carried out. The comparison between the groups is made with the distribution-free Mann-Whitney test. The level of significance is fixed at p < 0.05 (5 %). The mice of group N130 stay in the physiological sector with their blood gas results. Animals of group N100L show a respiratory acidosis. The preoxygenized P80L and P80S require a lower respiratory rate than non-preoxygenized animals independent of their weight. The medium arterial blood pressure of all groups sinks steadily while the heart rate increases at the same time. In the histological preparations of all groups including the control groups atelectasis, perivascular edemas, congestions and emphysemas can be seen. However, on what these pathological findings are based cannot be thoroughly explained. Therefore, mice should be preoxygenized 5 minutes prior to a ventilation. Thus, a respiratory rate of 80 per minute is sufficient for all weights. If not preoxygenized, a respiratory rate of 130 /min is suggested for animals up to 39 grams and approximately 110 /min for mice over 39 grams. With these settings the UNO Micro-Ventilator® is to be recommended for the ventilation of mice.