Category Archives: Transhuman News

In rivers and streams across the globe lives a tube-shaped carnivore. It paralyzes and captures prey with a crown of tentacles, then draws it in through its mouth (which also serves as its anus). This unsettling creature is a hydra, a freshwater-dwelling cnidarian no more than a half-inch long that eats mostly insect larvae and crustaceans. A hydras appearance and eating habits alone give it a sci-fi feel, but its ability to regenerate its body even its head from only a scrap of tissue or pile of cells raises it to another level.

Its one of these organisms thats thought to never die unless you try to kill it or, you know, starve it to death, Ali Mortazavi, a developmental biologist at the University of California, Irvine, said. A hydras regenerative abilities allow it to constantly replace bits of itself, so it doesnt succumb to things like old age or disease. Aside from the immortality perk, constant regeneration means a hydra doesnt have to sweat the small stuff, like losing body parts. Give it a few days and it will grow back anything.

Dr. Mortazavi and his colleagues have taken a big step in understanding how a hydra regenerates its head. Their research was published in Genome Biology and Evolution on Wednesday.

To investigate what makes this remarkable feat possible, the researchers looked at changes in gene expression whether a gene is copied from DNA into RNA throughout the course of hydra head regeneration. This control of gene expression is called epigenetic regulation. Hydras have a genome quite similar to that of species with little regenerative capacity, like humans, so its thought that epigenetic regulation plays a major role in making the hydras powers of regeneration possible.

The team discovered dynamic alterations in the regulation of stretches of DNA called enhancers. Enhancers increase the likelihood that a related gene will be copied from DNA into RNA. These enhancers were helping to ensure the expression of many genes, the team found, including those long known to be important for regeneration. Nobody knew hydras had these enhancer regions, said Dr. Mortazavi, who noted that the study put hydra in the same club as many other animals, including mammals.

The researchers then compared gene expression during head regeneration with gene expression during budding, a form of asexual reproduction where a hydra grows a polyp that is basically a copy of itself. That process requires growth of a second head, but the researchers found that a budding head forms in a very different way from a head regrowing after injury.

When I took a look at the trends in gene expression, the genes are kind of increasing slowly throughout the budding head development, but in regeneration, we noticed these sharp turns, said Aide Macias-Muoz, a developmental biologist at University of California, Santa Barbara, who was one of the study authors. A lot of genes are being turned on and then turned off and then turned back on. So even though the end result is the same, it looks like the trajectory is actually very different.

Dr. Mortazavi was also surprised to find that gene expression timing varied so much between head regeneration and budding. Clearly theres more than one way to make a head, he said.

The discovery of these enhancer regions and their role in hydra head regeneration also suggests that the evolution of enhancers predates the evolutionary divergence of cnidarians and bilaterians (animals with bilateral symmetry, like humans) around 750 million years ago. Erin Davies, a developmental biologist at the National Cancer Institute who studies regeneration but was not involved in the work, sees these findings as a reminder of the importance of studying ancient creatures like hydras.

They are really in a prime position for answering a lot of very fundamental questions in developmental biology, she said, including How did nervous systems evolve? How did you get bilateral symmetry?

This kind of work is also essential for the regenerative medicine field, Dr. Davies said, where a common goal is to restore diseased and injured tissues or even whole organs.

If you have a good handle on a paradigm in any animal system, she said, then you can start to think about how you might reverse engineer things in less regeneration-competent species, like mammals.

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Hydra DNA Reveals Theres More Than One Way to Regrow a Head - The New York Times

Introduction

Despite race being a socio-political system of categorization without a biologic basis, race has historically and continues to play a role in medical teaching and clinical decision making within health care. Race permeates clinical decision making and treatment in multiple ways, including: (1) through providers attitudes and implicit biases, (2) disease stereotyping and clinical nomenclature, and (3) clinical algorithms, tools, and treatment guidelines. While some diseases have higher prevalence among individuals with certain genetic ancestry, genetic ancestry is poorly correlated with commonly used social racial categories. The use of race to inform clinical diagnoses and decision making may reinforce disproven notions of race as a biological construct and contribute to ongoing racial disparities in health and health care. This brief provides an overview of the role of race in clinical care and discusses the implications for health and health care disparities and efforts to advance health equity.

Despite there being no biologic basis to race, the medical and scientific community have used race to explain differences in disease prevalence and outcomes. The Western concept of race arose as a system of hierarchical human categorization to support European colonialization, oppression, and discrimination of non-European groups. Within U.S. medical curricula, the concept of race led to theories of biological inferiority of people of color and White supremacy, which fueled an array of atrocities in medicine including forced sterilization efforts targeting Black and Native American women, the use of Henrietta Lacks cells for scientific research without consent or acknowledgement, and the infamous Tuskegee Syphilis study, among others. Although research has since disproven the existence of universal biologic differences by race, some recent scientific studies continue to suggest that genetic differences between racial groups may explain differences in health outcomes. For example, an article published in 2020 originally suggested that unknown or unmeasured genetic or biological factors may be contributing to increased severity of COVID-19 illness among Black people, although the article was later revised to clarify that the difference is most likely explained by societal factors. Recent research further suggests that measures of demographic characteristics and socioeconomic position may be more effective than genetic characteristics in explaining disparities in cardiovascular disease between Black and White adults.

There have been growing calls against using race as a factor to explain health differences without acknowledging the role of racism. Contemporary science has demonstrated that race is a social category with no basis in biology. Race is a poor proxy for genetic ancestry and large genetic studies have demonstrated more variation within defined racial groups (intra-racially) than there are between different racial groups (inter-racially). Within the medical and scientific community, there have been longstanding critiques of using racial classifications in diagnosis and treatment of disease. Recently, there have been calls for research studies and guidance in the medical community to name and examine the role of racism versus race as a key driver of health inequities to avoid perpetuating disproven understandings of biologic differences by race.

Although race is not tied to biologic differences, understanding differences in health and health care by race and ethnicity remains important for identifying and addressing disparities in health and health care that stem from racism and social and economic inequities. Complete and accurate race and ethnicity data is key for identifying disparities and taking action to address them. However, there are longstanding gaps and limitations in racial and ethnic data within health care. In addition to deficiencies in survey and administrative data, many institutions report gaps in electronic health record (EHR) data on race, with substantial misclassification of self-reported race and preferred language. The largest discrepancies between EHR demographic data and self-reported data are among individuals who identify as Hispanic.

A significant and longstanding body of research suggests that provider and institutional bias and discrimination are drivers of racial disparities in health, contributing to racial differences in diagnosis, prognosis, and treatment decisions. Prior work suggests that providers historically were more likely to perceive individual patient factors rather than provider or health system influences as causes for health disparities. For example, studies have found that providers view Black patients as less cooperative with medical treatment and that providers associate Hispanic patients with noncompliance and risky behavior. A 2015 systematic review of published studies showed that most health care providers appear to have implicit bias in terms of positive attitudes towards White people and negative attitudes towards people of color. While some studies have found no link between bias and provider treatment behaviors, others have demonstrated that provider bias correlates with poorer patient-provider interactions and is associated with disparities in pain management and empathy. Providers who endorse false beliefs about biological differences by race report lower pain for Black patients compared to White patients, which has been linked to systematic undertreatment for pain of Black patients. Similarly, compared to White patients in emergency departments, Hispanic and Asian patients are less likely to receive pain assessments and appropriate pain medication.

Research also shows that patients report being treated unfairly because of their race/ethnicity while accessing health care. For example, a 2020 KFF/the Undefeated survey of adults found that Black and Hispanic adults are more likely than White adults to report they were personally treated unfairly because of their race and ethnicity while getting health care in the past year. Black adults also are more likely than White adults to report negative experiences with health care providers, including feeling a provider did not believe they were telling the truth, being refused a test or treatment they thought they needed, and being refused pain medication. In addition, Black and Hispanic adults are more likely than their White counterparts to say it is difficult to find a doctor who shares their background and experiences and one who treats them with dignity and respect.

Some medical training approaches and materials use imprecise labels conflating race and ancestry, portray diseases through racial stereotypes, and rely on racial heuristics (i.e., mental shortcuts or associations) for teaching clinical diagnosis. Preclinical lectures and clinical vignettes for teaching use nonspecific labels (e.g., Black instead of Nigerian/Haitian and Asian instead of Chinese/Vietnamese/Pakistani) and may misuse race as a surrogate for genetic ancestry. In some cases, they inappropriately use race as a proxy for differences in socioeconomic status, health behaviors (such as diet), or other factors that may influence access to health care or risk of disease. In addition, lecture materials commonly present racial differences in disease burden without historical or social context, which may contribute to students connecting diseases with certain racial groups and ascribing differences to genetic predisposition. For example, preclinical lecturers often teach that recurrent lung infections in White individuals are indicative of cystic fibrosis, which may result in missed diagnoses of cystic fibrosis among Black patients. The hereditary condition glucose-6-phosphate dehydrogenase (G6PD) deficiency, which can cause severe anemia, affects individuals of all racial and ethnic backgrounds, with highest prevalence in Africa, the Middle East, and certain parts of the Mediterranean and Asia. However, lecturers and board materials teach students to have higher clinical suspicion for diagnosis of this deficiency in Black patients. In nearly all medical learning resources, Lyme disease is depicted predominantly on White skin and is often diagnosed much later when the disease has progressed to arthritic stages among Black patients. Other examples of connecting race to disease exist in medical textbooks. For example, Black skin is more commonly used to depict sexually transmitted diseases. A recently recalled textbook for nursing students published in 2017 suggested that there were racial differences in how patients experience and respond to pain. The text described Black patients as reporting higher pain intensity than other cultures, Hispanic patients as having wide expression of pain (some are stoic and some are expressive), Asian patients as valuing stoicism as a response to pain, and Native American patients as being less expressive both verbally and nonverbally. Beyond teaching materials, medical board examinations often test students based on race-based guidelines and heuristics.

Some disease names use racial or geographic terms that link diseases to certain groups or communities. For example, congenital dermal melanocytosis was formerly referred to as Mongolian spot. Similarly, Down syndrome was first described as Mongolism by a 19th century British physician who believed that patients with the genetic disorder resembled individuals of Mongolian descent. As another example, vancomycin infusion reaction was formerly called Red Man syndrome, evoking racist connotations against Indigenous American people. Clinical nomenclature has shifted towards more descriptive language, although in some cases, disease naming is tied to place of discovery. Disease names incorporating geography may still perpetuate racist-xenophobic sentiment. In 2015, the World Health Organization noted associating disease names with geography may result in backlash towards members of particular ethnic communities. This experience was seen in the recent use of the label China virus for the COVID-19 virus, which has been associated with an increase in public anti-Asian sentiment and Asian hate crimes, as well as an increase in depressive symptoms among individuals identifying with multiple Asian subgroups. Moreover, a recent KFF survey of Asian community health center patients found that one in three felt more discrimination based on their racial/ethnic background since the COVID-19 pandemic began in the U.S. and 15% said they had been accused of spreading or causing COVID-19.

While some diseases have higher prevalence among individuals with certain genetic ancestry, the practice of using race within clinical calculators and screening metrics may contribute to health disparities. Today, clinical calculators across multiple specialties assign differential risk for certain diseases or conditions based on race. Prior work has identified a range of examples of clinical calculators that use race (Appendix Table 1). One of the most well-known examples of this practice is within nephrology, where separate measures of kidney function (i.e., estimated glomerular filtration rates, eGFRs) are applied to Black patients compared to non-Black patients. However, similar examples are seen across medicine. For example, a common calculator used to predict success of vaginal birth after Cesarian (VBAC) section had a correction factor for both Black and Hispanic race that decreases the success of VBAC for Black and Hispanic patients by 67% and 68% respectively. This tool may bias providers into disproportionately counseling these patients towards undergoing a Cesarian section. Similarly, pulmonary function tests have a race correction factor, East Asian race is considered a major risk factor for neonatal jaundice, and a different Body Mass Index threshold is used to recommend diabetes testing among asymptomatic Asian and Pacific Islander patients. Given that race is an extremely inconsistent proxy for genetic ancestry, this use of race within clinical calculators may lead to both undertreatment and overtreatment of racialized individuals, and delays in diagnosis and clinical care.

Research shows that some clinical tools may be less effective or misused for certain populations. For example, pulse oximeters have low accuracy in measuring oxygen saturation in darker skin and are three times as likely to miss low oxygen levels in Black patients compared to White patients. Such discrepancies may contribute to delayed intervention and increased mortality for Black patients with COVID-19. In pediatrics, findings suggest that jaundice measurement tools (i.e., bilirubinometer for measurement of transcutaneous bilirubin) have varied reliability based on skin color, with underestimates of risk in lighter skin and overestimates in darker skin tone. Overestimates of bilirubin using transcutaneous measurements may result in unnecessary follow-up blood work (an invasive process for infants), increases in follow-up visits and commute to clinics, and increased infant caregiver distress. In lower resource settings where serum bilirubin measurement is unavailable and transcutaneous bilirubinometry continues to be the primary method for infant monitoring, underestimates of risk may result in delayed intervention for the life-threatening condition neonatal kernicterus, while overestimates of risk for hyperbilirubinemia may result in unnecessary prolonged hospital stays and treatment. In dermatology, the dearth of images depicting lesions on dark skin in medical and dermatologic textbooks and lack of representation of providers with darker skin in the specialty may result in reduced clinician ability to identify life-threatening dermatological presentation on people of color (e.g., sepsis, cellulitis, or severe drug reactions to medications). Skin cancer, while less common in Black and Hispanic patients, is often diagnosed later with subsequently lower survival rates. Fitzpatrick skin type (FS) is the most commonly used skin type classification system in dermatology. It was originally designed to describe the likelihood of skin to burn from UV light exposure but is misused by many providers to describe skin color as a proxy for race.

Preventing against racial bias will be important as use of artificial intelligence and algorithms to guide clinical decision-making continue to expand. The health care system is increasingly using artificial intelligence and algorithms to guide health decisions. Research has shown that these algorithms may have racial bias because the underlying data on which they are trained may be biased and/or may not reflect a diverse population. For example, one study found that an algorithm designed to identify patients with complex health needs resulted in Black patients being assigned the same level of risk as White patients despite being sicker. This unintended bias occurred because of underlying racial bias in how the algorithm was designed, implemented, and interpretedthe algorithm used health care costs to predict health care needs, but Black patients have lower health care costs in part because they face greater barriers to accessing health care. Other examples have found that skewed dermatological datasets result in less accurate models and decreased ability to diagnose skin conditions among darker skin tones. However, research also suggests that carefully designed algorithms can mitigate bias and help to reduce disparities in care.

Race also factors into some medication prescribing decisions, but the use of race is often based on limited evidence from small studies and may result in inappropriate dosing and treatment. In 2005, the U.S. Food and Drug Administrative approved the drug BiDil as a race-specific drug to treat heart failure among African Americans. It was subsequently critiqued for misguided marketing due to using race as a proxy for genotype, which was not evaluated in the study from which conclusions were drawn, although it remains approved as a race-based drug today. There are additional examples of race-based prescribing guidelines. For example, hydrochlorothiazide is recommended as first line hypertension therapy for Black patients based on Joint National Committee (JNC) Hypertension guidelines, as opposed to ACE inhibitor therapy for all other groups due to presumed inefficacy of these agents among Black patients. Eltrombopag, a drug used to treat thrombocytopenia, has a lower recommended starting dose for East Asian patients compared to all other patients. Similarly, the Food and Drug Administration recommends a lower starting dose for Crestor (a statin, used to lower lipid levels) for Asian patients based on a gene that confers metabolic variability, despite the understanding that this gene may be prevalent among any population. There has been ongoing discussion around race-based dosing and the utility of race-based genetic screening for drugs such as warfarin (commonly used for anticoagulation therapy) and abacavir for HIV treatment. Medical community viewpoints on race-based prescribing vary. For example, a study of American cardiologists found that many providers believe race-based drug labels in treatment of heart failure may help prescribe effective medications sooner, while others expressed concerns that considering race could potentially harm patients by resulting in some patients not receiving the drug.

The use of race in the emerging field of pharmacogenomics has come under increasing scrutiny. Pharmacogenomics explores the relationships between genes and drug effects and is viewed as a way to potentially personalize medical therapy. Pharmacogenomics research often uses race to guide decisions about genetic screening prior to using certain drugs to prevent against adverse drug events based on the assumption that certain racial categories may have high or low prevalence of certain genes. Proponents argue that race-based targeting in the field of pharmacogenetics is useful to propel personalized medicine for patient care at the individual level. However, critiques of race-specific therapies express concerns around attempting to address health disparities through commercial drug development versus examining upstream structural factors that may explain differences in treatment response. Moreover, as noted, genetic variation within certain racial/ethnic groups can exceed variation across racial/ethnic categories, suggesting limited utility of this approach and that it may run counter to personalized medicine by treating people based on groupings that have limited genetic association. Current work has limited representation from communities of color, resulting in less extrapolatable, premature recommendations for clinical screening for diverse communities. In addition, inequities across the continuum of drug development and clinical trial participation and evaluation may exacerbate existing disparities in medication access for communities of color, including decreased access to novel, high-cost medications and lower-cost generic therapies.

The use of race within clinical decision making and treatment may reinforce disproven concepts of racial biology and exacerbate health inequities. Race continues to permeate medical teaching and clinical decision making and treatment in multiple ways, including: (1) through providers attitudes and implicit biases, (2) disease stereotyping and nomenclature, and (3) clinical algorithms and treatment guidelines. Racial bias among providers may contribute to poorer quality of care and worse health outcomes. Racial stereotyping of disease and use of race in clinical algorithms and treatment guidelines may lead to errors in clinical diagnosis and management (overtreatment or undertreatment and other delays in clinical care), which may perpetuate and potentially worsen health disparities. Moreover, continued use of race as a biological concept limits examination and understanding of social drivers of health inequities, including racism, and contributes to ongoing racial bias and discrimination among providers.

There have been growing efforts within the medical community to re-evaluate and revise practices around the use of race within clinical care and efforts to move towards race-conscious (as opposed to race-based) medicine. In 2020, the American Medical Association (AMA) adopted new policies to recognize race as a social construct and, as part of these policies, encourages medical education programs to recognize the harmful effects of using race as a proxy for biology in medical education through curriculum changes that explain how racism results in health disparities. In September 2020, the House Ways and Means Committee announced a Request for Information around the misuse of race in clinical care. The Agency for Healthcare Research and Quality (AHRQ) similarly announced in March 2021 a Request for Information on the use of clinical algorithms that have the potential to introduce racial/ethnic bias into healthcare delivery. A subsequent Ways and Means final report released in October 2021 found that professional societies suggest more research (with evaluation of unintended consequences of removing race correctors) is needed before decisions can be made, as a growing number of institutions have removed race from clinical calculators. For example, in the past year-and-a-half, Mass General Brigham hospital, the University of Washington, Vanderbilt University, and NYC Health and Hospitals have all removed race corrections from kidney function estimates. The UC Davis School of Medicine also eliminated race-based reference ranges from renal function estimates, followed shortly by UCSFs release of a new approach to estimate kidney function without race. Moreover, both the American Society of Nephrology and National Kidney Foundation have outlined approaches to diagnose kidney disease without race. In November 2021, the New York City Department of Health launched a Coalition to End Racism in Clinical Algorithms, pledging to end race adjustment in at least one clinical algorithm and to create plans for evaluation of racial inequities and patient engagement. Additionally, some commonly used medical calculators have made use of race correction factors optional, while others have removed them entirely (see Appendix Table 1). In contrast, other institutions have held off on making changes to clinical calculators or guidelines, noting potential downstream implications for other aspects of clinical care and management.

Looking ahead, continued education of health care providers and students to eliminate beliefs of biologic differences by race, improving pedagogy around distinctions between race and genetic ancestry, and reducing racial bias and discrimination will be important, as will efforts to increase the diversity of our health care workforce. Moreover, continued careful evaluation of how race factors into clinical decision-making through clinical guidelines, tools, and algorithms will be important for mitigating biased decision making, particularly as the use of artificial intelligence and machine-driven algorithms to guide clinical decisions expand.

Michelle Tong is a fourth year medical student at the University of California, San Francisco, completing a health policy fellowship with the Kaiser Family Foundation. Samantha Artiga serves as Vice President and Director of the Racial Equity and Health Policy Program at KFF. The authors thank Dr. Louis H. Hart III and Dr. Monica Hahn for their expertise and subject matter review. Dr. Louis Hart is the Medical Director of Health Equity for Yale New Haven Health System and Assistant Professor of Pediatric Hospital Medicine at the Yale School of Medicine. Dr. Monica Hahn is the Co-Founder of the Institute for Healing and Justice in Medicine and Associate Clinical Professor at UCSF in the Department of Family and Community Medicine.

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Use of Race in Clinical Diagnosis and Decision Making: Overview and Implications - Kaiser Family Foundation

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Annu Int Conf IEEE Eng Med Biol Soc. 2021 Nov;2021:2437-2443. doi: 10.1109/EMBC46164.2021.9630460.

ABSTRACT

Among males, prostate cancer (Pca) is the cancer type with the highest prevalence and the second leading cause of cancer deaths. The current screening methods for prostate cancer lack effectiveness such as prostate-specific antigen (PSA) and digital rectal exam (DRE). Machine learning models have been used to predict Pca progression, Gleason score, and laterality. In this research paper, we have employed novel Machine learning techniques such as Bayesian approach, Support vector machines (SVM), Decision Trees, Logistic Regression, K-Nearest Neighbors, Random Forest and AdaBoost for detecting malignant prostate cancers from benign ones. Moreover, different feature extracting strategies are proposed to improve the detection performance and identify potential genomic biomarkers. The results show the Lasso feature set yielded high performance from the models with SVM achieving exemplary classification accuracy of 97%. The Lasso and SVM combination reported many significant biomarker genes and gene mutations including but not restricted to CA2320112, CA2328529, and CA2436168.

PMID:34891773 | DOI:10.1109/EMBC46164.2021.9630460

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Identification of Significantly Expressed Gene Mutations for Automated Classification of Benign and Malignant Prostate Cancer - DocWire News

More than 2.5 million Americans have a chronic condition arising in early childhood that can negatively impact their education, job performance and employability well into adulthood.

There is no known cure, and existing treatments are often minimally effective. Yet for those with persistent, developmental stuttering, there is new hope, thanks to groundbreaking research led by scientists at Vanderbilt University Medical Center in Nashville, Tennessee, and Wayne State University in Detroit, Michigan.

In two papers published this week, Jennifer "Piper" Below, PhD, and Shelly Jo Kraft, PhD, describe a "genetic architecture" for developmental stuttering and report the discovery of new genetic variations associated with the condition.

The researchers said that these findings, which were published in The American Journal of Human Genetics andHuman Genetics and Genomics Advances, and studies like them have the potential to identify therapeutic directions that could improve outcomes for people who stutter.

"It's clear that in populations, stuttering is polygenic, meaning that there are multiple different genetic factors contributing to and protecting people from risk," said Below, associate professor of Medicine at VUMC. "That was something that had not been clearly shown before these studies."

The new revelations will have a huge impact on people who stutter and on the parents of children affected by the condition, predicted Kraft, associate professor of Communication Sciences and Disorders and director of the Behavior, Speech & Genetics Lab at Wayne State University.

"It's a piece of themselves that they can then understand," she said, "instead of living a lifetime of experiencing this difference in their speech and never knowing why."

With the help of colleagues in Ireland, England, Israel, Sweden, Australia and throughout the United States, Kraft has collected blood and saliva samples for genetic studies from more than 1,800 people who stutter, including more than 250 families with three generations of stuttering.

But while that effort, called the International Stuttering Project (www.theinternationalstutteringproject.com), identified new genetic variations, or variants, associated with developmental stuttering, it was not sufficiently "powered" to reveal the complexity of the condition. There simply were not enough people in the studies.

That's where Below comes in. She utilized a key VUMC resource, BioVU, one of the world's largest repositories of human DNA linked to searchable, electronic health information. BioVU has enabled researchers to conduct GWAS, or genome-wide association studies to probe the genetic underpinnings of a wide range of diseases.

Stuttering, however, is a condition that is rarely mentioned or given a diagnostic code in the medical record. People aren't hospitalized for stuttering. "We had to come up with some clever new ways to try to capture that missing code," Below said.

From confirmed cases of developmental stuttering, the researchers constructed a "constellation" of diagnostic codes for other conditions such as attention-deficit hyperactivity disorder (ADHD) and autoimmune reactions to infections that co-occur with stuttering more frequently than would be expected by chance.

Then, using machine learning techniques, they created an artificial intelligence tool that used the presence of these "phenotypes" recorded in the electronic health record to predict those who were likely to stutter, "even in the absence of having a direct note about their stuttering in their medical record," Below said.

Supported by $3.5 million, five-year grant awarded in 2018 by the National Institute on Deafness and Other Communication Disorders, part of the National Institutes of Health, the researchers demonstrated that their stuttering prediction model positively predicted the presence of stuttering more than 80% of the time.

The research also turned up a stuttering-related gene implicated in autism-spectrum disorder, as well as genetic variants that affect the regulation of sex hormones. The latter finding may help explain why boys are more likely to stutter, and why women who stutter are more likely to recover.

Some correlations between traits may be spurious, Below noted. But if the researchers establish genetic connections between stuttering and other traits such as ADHD, those findings could open up avenues for treating both conditions at the same time, Kraft said.

Researchers from private speech clinics in Dublin, Ireland, Curtin University in Perth, Australia, and the University of North Carolina at Chapel Hill contributed to the research. The National Stuttering Association, Irish Stammering Association and other organizations have supported the research by sponsoring collections.

VUMC co-authors were Hannah Polikowsky, Douglas Shaw, Dillon Pruett, Hung-Hsin Chen, PhD, MS, Lauren Petty, and Robin Jones, PhD, associate professor of Hearing and Speech Sciences. Co-authors from Curtin University included Janet Beilby, PhD, and Kathryn Viljoen.

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VUMC: Gene Discoveries Give New Hope To People Who Stutter - Cannon Courier

Introduction

In addition to its high lethality, stroke is also recognized as a vital contributor to disability and cognitive impairment.1,2 Among them, cognitive impairment significantly delays functional recovery and affects the life quality of patients,35 as well as increases healthcare costs. Therefore, early and accurate identification of risk factors associated with cognitive impairment to improve the prediction of PSCI is critical for optimizing the treatments.

Serum homocysteine, as a kind of sulfur-containing amino acids, is identified as a reactive vascular injury amino acid due to the strong oxidative effects on vascular endothelial cells and subsequent vascular lesions.6 Meanwhile, serum Hcy levels are affected by several factors, including age, sex (male), pregnancy, high methionine-rich protein diet, vitamin (such as folic acid, vitamin B6, and B12) deficiency, renal failure,7,8 genetic mutation including heterozygous/homozygous cystathionine- synthase (CBS) gene and MTHFR gene, medication (such as methotrexate and niacin) use, and so on,9,10 all of which can contribute to HHcy. As a risk factor for cardiovascular diseases, Hcy is also closely related to multiple neurological diseases such as stroke and cognitive decline.11,12 In recent years, emerging evidence has been discovered to support the link between homocysteine and PSCI,13,14 among which inflammatory pathway is regarded as one of the essential underlying mechanisms. As an acute-phase protein and the most sensitive biomarker of nonspecific inflammatory response, hsCRP is elevated in patients with cognitive impairment,15,16 and can independently predict PSCI,17 thus exhibiting the potential for evaluating cognitive disorders in clinics.18

To our knowledge, no individual study has analyzed the relationships among homocysteine, hsCRP and PSCI. In this study, we aim to investigate their relationship based on CNSR-III in patients with AIS and TIA.

We obtained the data from the Impairment of Cognition and Sleep (ICONS) subgroup of CNSR-III.19 The ICONS study is a multicenter (40 hospitals) prospective registry. It recruited AIS or TIA inpatients (within 7 days of onset) between August 15, 2015 and January 2018, with 1-year follow-up finished in March 2019 and 2625 patients were included. Patients who met the preplanned inclusion criteria were eligible: age over 18 years old; in-hospital AIS or TIA without any history of severe cognitive impairment prior to stroke or any comorbidity that could interfere with cognitive assessment. After excluding 825 individuals with missing information on Hcy,84 individuals with missing information on hsCRP at baseline and 250 individuals without MoCA assessments at 3-month follow-up, we finally included 1466 subjects for subsequent analysis (Figure 1).

Figure 1 Patient Flowchart.

Prior to data collection, we have obtained approval from the ethics committee of Beijing Tiantan Hospital, and signed informed consent from all included patients.

Patients with AIS or TIA with complete data of baseline Hcy and hsCRP levels as well as cognitive evaluation at 3-month by trained neurologists were included. Other baseline characteristics including age, gender, body mass index (BMI) as well as past history were collected by a professional physician during the interview. We dichotomized the levels of Hcy and hsCRP as follows, normal Hcy (<15 mmol/L), HHcy (15 mmol/L),20 normal hsCRP (<3 mg/L), and high hsCRP (3 mg/L).21

The MoCA was employed to detect PSCI and assess global cognition.22 Specifically, a patient with a MoCA score below 26, or less than 12 years of education and a MOCA score below 25 was considered cognitively impaired.23 The primary outcome was the prevalence of PSCI at 3 months after the onset of AIS or TIA.

The data analyses were conducted using SAS 9.4 (SAS Institute Inc, Cary, NC). Continuous variables were exhibited as medians with interquartile ranges and categorical variables as percentages. For comparisons, we used one-way analysis of variance or KruskalWallis test for the continuous variables and chi-square statistics for the categorical variables. We employed multivariable logistic regression analysis to evaluate the correlations among hsCRP, Hcy, and PSCI. Results were reported as odds ratios (ORs) with 95% confidence interval (95% CI). P < 0.05 was considered statistically significant.

We selected 1466 eligible patients from the 2625 patients in the ICONS study with a median age of 62 years old. Four hundred and fourteen (28.24%) of them were female. Compared with patients excluded, the included patients had higher rates of history of hyperlipidemia but lower BMI, as shown in Table 1.

Table 1 Baseline Characteristics of Patients Included versus Not Include

Baseline characteristics of study patients are displayed in Table 2. Among participants included in our study, 466 (31.79%) patients had higher hsCRP levels. Compared with the NCRP (normal high-sensitivity C-reactive protein) group, more patients in the HCRP (high high-sensitivity C-reactive protein) group had elevated Hcy levels. The median Hcy levels were 16.5 mol/L (NCRP group) and 16.6 mol/L (HCRP groups), respectively. Participants in the HCRP groups were older, more likely to have higher proportions of history of hypertension and diabetes, had higher systolic blood pressure at admission, furthermore, they had higher baseline white blood cell (WBC) counts and Vitamin B12 levels. While, in the HHcy group, patients with increased hsCRP concentrations were older, had higher WBC counts, folate, and vitamin B12 levels, as well as higher baseline NIHSS. While in the NHcy group, patients with increased hsCRP concentrations were older, more likely to have higher proportions of history of hypertension and diabetes, had higher baseline WBC counts and NIHSS score.

Table 2 Baseline Characteristics of Participants Stratified by Hcy and HsCRP Levels

Table 3 exhibits the comparison of outcomes between the groups. No significant differences of the PSCI were found between the NCRP and HCRP groups after adjusting for potential variables (crude OR: 1.54,95% CI: 1.231.92, p < 0.001; adjusted OR: 1.27, 95% CI: 0.991.62, p = 0.06). In the HHcy group, patients with high hsCRP level were significantly likely to suffer from cognitive impairment, even if the confounding factors were controlled (crude OR: 1.71,95% CI: 1.292.27, p < 0.01; adjusted OR: 1.42, 95% CI: 1.041.93, p = 0.03). However, no similar correlation in the NHcy group was identified (crude OR: 1.30, 95% CI: 0.911.87, p = 0.15; adjusted OR: 1.05, 95% CI: 0.701.58, p = 0.80). When comparing the four groups directly, only the high hsCRP and high homocysteine groups were related to cognitive impairment, but this association was attenuated after adjustment for potential confounders (crude OR: 1.48, 95% CI: 1.092.01, p = 0.01; adjusted OR: 1.23, 95% CI: 0.881.72, p = 0.23). Furthermore, after classifying patients according to age, sex, and TOAST criteria, those who were older (adjusted OR: 1.45, 95% CI: 1.022.05, p = 0.04), male (adjusted OR: 1.67, 95% CI: 1.052.65, p = 0.03), or large-artery atherosclerosis (LAA) classification (adjusted OR: 1.96, 95% CI: 1.053.66, p = 0.04) were more likely to have cognitive impairment if presenting high homocysteine and high hsCRP levels at the same time (Table 4). Of note, no significant interaction for the impact on PSCI was observed in subgroups stratified by age, sex, or TOAST classification (P interaction=0.9537,0.6288 and 0.8233 respectively).

Table 3 Multivariate-Adjusted Odd Ratios (ORs) for Cognitive Impairment According to hsCRP Levels and HCY at 3 Month

Table 4 Multivariable Adjusted Odd Ratios (OR) of Subgroup Analysis for Cognitive Impairment According to hsCRP Levels

Significantly increased risk of cognitive impairment was only found in patients with both elevated hsCRP and Hcy levels in our study. The associations among inflammation, homocysteine, and cognitive impairment were significant in patients who were male, older (over 65 years), and those with the TOAST classification of LAA type. For each MoCA subgroup, no significant interaction for the impact on PSCI was observed in subgroups stratified by age, sex, or TOAST classification.

Previous reports indicated hyperhomocysteinemia as a unique risk factor for cognitive impairment,24,25 Sachdev et al in 2003 found that high Hcy level was associated with cognitive impairment, especially in frontal executive functions. In 2019, a prospective multi-center registry conducted by Zhu et al showed that a risk model based on combined tHcy, rheumatoid factor (RF), and matrix metalloproteinase-9 (MMP-9) might enhance the predictive power for cognitive impairment after stroke.26 Furthermore, an observational study discovered that homocysteine level was correlated with cerebral microbleeds (CMBs) in cognitively impaired patients.27 Moreover, a research conducted in 2013 found that hsCRP combined with Hcy could predict the prognosis of AIS patients among the Chinese mainland populations.28

High concentrations of homocysteine can directly exert toxic effects on neurons, which may be caused through amino acid-induced toxicity, reactive oxidative stress (ROS), endoplasmic reticulum, and N-methyl-D-aspartate receptor (NMDAr)-mediated neurotoxicity, leading to neuronal death.2932 In addition, homocysteine may cause vascular endothelial function damage and alter permeability of bloodbrain barrier, resulting in cerebral small vessel disease. Combined with the above findings, we speculate that Hcy induces cognitive dysfunction through direct effects on glutamatergic neurotransmission and endothelin, indirect inhibition of methylation processes, enhancement of amyloid neurotoxicity, and promotion of tau phosphorylation.33 In addition, previous studies have found that endothelial inflammation under high Hcy conditions promoted vascular injury,34 which in turn led to cognitive impairment. However, the underlying mechanisms remain obscure. On the one hand, Hcy can stimulate CRP expression through ROS and mitogen activated protein kinase (MAPK) signaling pathways,35 which in turn activates NF-B and further promotes inflammation in rat vascular smooth muscle cells.36 On the other hand, homocysteine also enhances the expression of NMDAr,35 thus stimulating CRP production and triggering inflammatory responses.37 Finally, Hcy has been shown to promote neuroinflammation and microglia activation through STAT3 activation subsequent to the ischemic stroke.38 Meanwhile, it has been reported that chronic mild hyperhomocysteinemia could cause damage on nuclear acids and protein, as well as ultrastructural alterations in the cerebral cortex in an inflammation-dependent manner.39

In subgroup analysis, for patients with both high homocysteine and hsCRP levels, those who were older, male, with a TOAST classification of atherosclerosis type had a higher risk of cognitive impairment compared to those with normal hsCRP levels. Age independently influences MoCA score,3 and high age generally reflects a high level of chronic inflammation in the body because CRP level increases with age.40 Moreover, female stroke patients seem to have a worse clinical outcome due to distinct hormone levels.41,42 In addition, homocysteine is an independent risk factor for atherosclerosis,43 which may be attributed to increased collagen synthesis, oxidative damage, endothelial dysfunction, and degradation of elastic material. Meanwhile, CRP is directly involved in the progression of atherosclerosis, a typical chronic inflammatory disease,44,45 by participating in multiple inflammatory processes.46 In light of the above findings, we examined a stratified analysis of age, sex, and TOAST classification in this study, but no interactions were found.

There are several limitations in our study. First, part of the patients in this study experienced a more than 24 h time period from onset to admission, and thus, their CRP and Hcy levels on admission could not accurately reflect the authentic situation at the time of stroke. Secondly, we only obtained baseline Hcy and CRP levels without any follow-up measures, which made it impossible to study the association between changes in hsCRP and Hcy and cognitive impairment. Thirdly, we stratified the patients into groups according to the hsCRP and Hcy level and make comparisons of clinical characteristics between groups, which will cause the problem of increased type 1 error by multiple comparison. Fourthly, genetic analysis was not included in this study, while MTHFRTT homozygote for homocysteine genotype was confirmed to be related to the increased homocysteine level.27 Finally, bias existed when selecting hospitalized patients. Some older patients with other serious diseases may refuse admission at an early stage, and they may have higher levels of both homocysteine and inflammation.

Our study shows that in patients with hyperhomocysteine post AIS and TIA, high hsCRP concentrations increase the risk of cognitive impairment.

Hcy, homocysteine; hsCRP, high sensitive C-reaction protein; AIS, acute ischemic stroke; TIA, transient ischemic attack; PSCI, post-stroke cognitive impairment; ICONS, Impairment of Cognition and Sleep; CNSR-3, China National Stroke Registry-3; MoCA, Montreal Cognitive Assessment; NIHSS: National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; TOAST: Trial of Org 10172 in Acute Stroke Treatment, LAA, large artery atherosclerosis, CE: Cardioembolism; SAA: small-artery occlusion; BMI, body mass index; SBP, systolic blood pressure; IQR, interquartile range; OR, odds ratio; CI, confidence interval.

Data are available on reasonable request.

This study was approved by the medical Ethics Committee of Beijing Tiantan Hospital (No.: KY2015-001- 01). All the study participants provided informed consent to take part in this study, in accordance with the Declaration of Helsinki.

We thank all study participants, of the survey teams at participating hospitals of the Third China National Stroke Registry, and the project development and management teams at the Beijing Tiantan Hospital.

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

This work was supported by grants from National Key R&D Program of China (2016YFC0901002), grants from the National Natural Science Foundation of China (81870905, U20A20358).

The authors report no conflicts of interest in this work.

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Relationship among Homocysteine, Inflammation in AIS | NDT - Dove Medical Press

90 Day Fianc: Before the 90 Daysreturned with a new season on Dec. 12, 2021, with seven new couples for fans to watch. The cast of season 5 also includes the first little person Alina to appear within the90 DayFiancfranchise. Twenty-seven-year-old Alina lives in St. Petersburg, Russia, but her boyfriend, Caleb, is American.Before the 90 Dayswill show the ups and downs of their relationship as they navigate the waters of international dating.

Besides being the first little person to appear on 90 Day Fianc: Before the 90 Days, Alina also has a different story about how she and Caleb met. Most couples onBefore the 90 Daysmeet through international dating sites as they actively search for love. Alina and Caleb met when they were just teenagers. Caleb wanted to meet some potential friends before leaving for an extended trip to Russia. Thats when he and Alina connected in an international chatroom.

However, the meeting never materialized, but the two connected several years later. Now, theyve discovered they want something deeper than a friendship, so both of them will travel to Turkey to finally meet in person.

RELATED: 90 Day Fianc: Before the 90 Days Season 5 Couples: Who Are Gino and Jasmine?

In theBefore the 90 DaysSeason 5 premiere episode, Alina talks about her medical condition known as Diastrophic Dysplasia.

Alina explains, Its a form of dwarfism. Its rare and it affects everyone differently. For a child to be born with this type of dwarfism both parents have to be carriers of the gene. It can affect your joints and, of course, your stature. My hands and my feet look pretty different too, but I dont think the disability is a problem. In many areas of my life, I try to do everything, really.

According toJohn Hopkins Medicine, Diastrophic dysplasia can affect the development of body parts including the hands, face, ears, feet, hips, legs and spine. People with diastrophic dysplasia are generally shorter than average in height.

Just like the condition affects everyone in different ways, doctors use different treatment methods depending on the symptoms the person exhibits.

However, Alina doesnt let the disorder hold her back. Im pretty comfortable in my body. Ive already accepted the fact that I dont look like everyone else and Im just trying to rock what I have. But there are things that are hard to do. With my hands, its a bit hard to do some things because my fingers dont really bend. I cant walk a lot. So, I use a wheelchair for longer distances, she explains inBefore the 90 Days.

RELATED: 90 Day Fianc: Before the 90 Days Season 5: Fans Accuse Ella of Fetishizing Asian Culture

In theBefore the 90 DaysSeason 5 Episode 1, Alina explains that her parents often baby her and her sister. However, due to her disorder, she gets the brunt of the worry from her parents. Neither are thrilled Alina is traveling to Turkey to meet a man shes never met in person before. However, she explains her friend Elijah plans to accompany her to help her with anything she might need.

It looks like Alina and Caleb finally meet in person inBefore the 90 DaysSeason 5 Episode 2. The show airs on Sunday nights at 8 P.M. ET and streams on discovery+.

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'90 Day Fianc: Before the 90 Days': Everything to Know About Alina's Rare Medical Condition Diastrophic Dysplasia - Showbiz Cheat Sheet

Experimental compound, which has received orphan drug and pediatric rare disease designations from the FDA, displays effectiveness in treating symptoms of Autism and Alzheimers disease.

An extensive international study led by Tel Aviv University found that an experimental drug which has been awarded orphan drug designation by the FDA for future treatment of a rare development disorder can also treat a variety of symptoms relating to autism, intellectual disability, and Alzheimers disease.

The experimental drug, NAP, was discovered in the lab of Prof. Illana Gozes of the Tel Aviv University Sackler Medical Schools Department of Human Molecular Genetics and Biochemistry. In recent years, the FDA has granted the experimental drug with orphan drug designation and pediatric rare disease designation for treatment of a rare developmental disorder called ADNP syndrome, which can cause a variety of symptoms, among them, hallmark features are intellectual disability and autism spectrum disorder.

In the current study, a team of researchers led by Prof. Gozes developed an innovative lab model and found that NAP can be effective in treating a broad spectrum of symptoms of ADNP syndrome, which is caused by mutations in the ADNP gene which is essential to cerebral development and protecting cerebral brain cells. Previous studies showed that ADNP syndrome is related to Alzheimers disease and certain types of mental disabilities, developmental delays, and autism.

Prof. Illana Gozes. Credit: Jonathan Blum, Tel Aviv University

Ramot, Tel Aviv Universitys technology commerce company filed a number of patent applications to protect the technology and its implementation and, in collaboration with Prof. Gozes, is raising funds to finance further clinical research. Similarly, Ramot is in discussions regarding commercial collaboration with pharmaceutical companies. Were excited by this new discovery and believe that this is groundbreaking technology that will remedy a variety of symptoms and disabilities in a broad spectrum of orphan diseases, said Prof. Keren Primor Cohen, CEO of Ramot.

The study, which is the culmination of the MD/PhD student Dr. Gideon Carmons doctoral research, was joined by a team of researchers from Prof. Gozess lab: Dr. Shlomo Sergovich, Gal Hacohen-Kleiman, Inbar Ben-Horin-Hazak, Dr. Oxana Kapitansky, Alexandra Lubincheva, and Dr. Eliezer Giladi. The team was further joined by Dr. Moran Rubinstein, Prof. Noam Shomron, and Guy Shapira of TAUs Sackler Faculty of Medicine, and Dr. Metsada Pasmanik Chor of Tel Aviv Universitys George S. Wise Faculty of Life Sciences. Researchers from the Czech Republic, Greece, Germany, and Canada also participated. The article was published in the prestigious journal Biological Psychiatry.

Prof. Gozes explained that: NAP, in fact, comprises a short segment of the normal ADNP protein. We previously found that treatment using NAP corrects the function of human nerve cells afflicted with ADNP syndrome in a laboratory test-tube. In this study, we sought to examine the efficacy of NAP in treating various aspects of the syndrome using a model with the most harmful mutation, which allowed us to view brain development and facilitate remedying of behavioral problems.

The study, which examined a model using mice with ADNP syndrome, used objective methods to analyze behavior, electrical activity, and to further identify select protein contents in the brain. The researchers found that the mice suffering from ADNP syndrome demonstrated a broad spectrum of pathological outcomes, including increased rates of neonatal death immediately after birth, slowed development and aberrant gait, primarily among females, as well as poor voice communication.

Cerebral examinations demonstrated additional findings: A relatively small number of synapses the points of contact tween nerve cells, impaired electrophysiological activity demonstrating a low potential for normal cerebral arousal, as well as precipitates (aggregates) of the Tau protein in young mice, similar to those in the brains of elderly Alzheimers disease patients.

For most of these symptoms, the researchers examined the effect of the future medicinal substance NAP made of a short and normal segment of the ADNP protein, the same protein that is impaired because of the mutation. Prof. Gozes: In the past, we have found that NAP corrects impaired functioning of ADNP that has mutated in the nerve cell model in the culture. We now examined its effect in vivo in animals modeling the syndrome (ADNP mutation). To our amazement and joy, we discovered that treatment using NAP normalizes the functioning of these mice for most of the symptoms indicated above!

Researchers further sought to identify in the blood of the mice, a clear biological indicator of ADNP syndrome that will enable diagnosis of this severe disease and effective monitoring of treatment using a simple blood test. With the help of genetic sequencing technologies, they identified an anomaly in a manner characteristic only of females as well as a method for repair using NAP on five proteins (at the messenger RNA level). These findings matched the changes discovered in white blood cells of children suffering from ADNP syndrome. One of the indicators discovered is FOXO3 a protein with an important role in generating cerebral synapses and healthy aging.

Prof. Gozes summarized: In this study, we examined the effect of the ADNP genes most prevalent mutation in a broad spectrum of aspects and found extensive impairment in physical and cerebral functioning parallel to the symptoms of autism, developmental delay, mental disability, and Alzheimers disease in humans. Similarly, we examined the potential use of the NAP drug for treating these diseases, and discovered that it is effective against most of these symptoms in lab models. This study is an important milestone on the way to developing a drug, or drugs, that will help children with autism stemming from genetic mutations, as well as Alzheimers patients.

Reference: Novel ADNP Syndrome Mice Reveal Dramatic Sex-Specific Peripheral Gene Expression With Brain Synaptic and Tau Pathologies by Gidon Karmon, Shlomo Sragovich, Gal Hacohen-Kleiman, R. Anne McKinney, Moran Rubinstein and Illana Gozes, 27 September 2021, Biological Psychiatry.DOI: 10.1016/j.biopsych.2021.09.018

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Groundbreaking Experimental Compound Displays Effectiveness in Treating Symptoms of Autism and Alzheimers Disease - SciTechDaily