Men's Health : the healing of Prometheus

This thesis investigates the state of men's health, which is in silent crisis. The male mortality rate is 60% higher then the female mortality rate in Canada. Furthermore it is higher for all 10 leading causes of death. The difference in life expectancy is over 5 years between men and women. Contributing to their early demise are so-called preventable deaths, homicide, suicide, vehicle accidents and work accidents which are much more prevalent among males than females. In the U.S. from infancy, males die and suffer serious illnesses at greater rates than females. In fact between the age of 15 and 24, male die at a rate more than three times that of females. This constitutes a silent health crisis---silent because it is not acknowledged, it is in fact, ignored. In Canada there are five Centres of Excellence devoted to women's health---yet there are none for men's health, which is far worse. In the U.S., the morbidity and mortality rates are proportionally similar. There are eleven Specialized Centers of Research for Women's Health, and none for men. We will explore in this thesis both the reasons for men's ill health relative to women's, and the paradox of the silence. Three major theoretical perspectives: the bio-medical, the environmental, and lifestyle, are examined extensively, as are gender specific theories concerning the role that masculinity plays in contributing to male health. Lastly, I present recommendations for improving men's health. Not only is there an appalling loss of men's lives and to a lesser extent women's for many reasons, but also it is extremely expensive. The economic costs of male potential years of life lost in 2001 (U.S. data), amounted to $329,836, million dollars per annum. This money would be better invested in preventive care and Centers of Excellence devoted to men's health

GARS- related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment

The majority of patients with spinal muscular atrophy (SMA) identified to date harbor a biallelic exonic deletion of SMN1. However, there have been reports of SMA- like disorders that are independent of SMN1, including those due to pathogenic variants in the glycyl- tRNA synthetase gene (GARS1). We report three unrelated patients with de novo variants in GARS1 that are associated with infantile- onset SMA (iSMA). Patients were ascertained during inpatient hospital evaluations for complications of neuropathy. Evaluations were completed as indicated for clinical care and management and informed consent for publication was obtained. One newly identified, disease- associated GARS1 variant, identified in two out of three patients, was analyzed by functional studies in yeast complementation assays. Genomic analyses by exome and/or gene panel and SMN1 copy number analysis of three patients identified two previously undescribed de novo missense variants in GARS1 and excluded SMN1 as the causative gene. Functional studies in yeast revealed that one of the de novo GARS1 variants results in a loss- of- function effect, consistent with other pathogenic GARS1 alleles. In sum, the patients’ clinical presentation, assessments of previously identified GARS1 variants and functional assays in yeast suggest that the GARS1 variants described here cause iSMA. GARS1 variants have been previously associated with Charcot- Marie- Tooth disease (CMT2D) and distal SMA type V (dSMAV). Our findings expand the allelic heterogeneity of GARS- associated disease and support that severe early- onset SMA can be caused by variants in this gene. Distinguishing the SMA phenotype caused by SMN1 variants from that due to pathogenic variants in other genes such as GARS1 significantly alters approaches to treatment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/1/ajmga61544_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154914/2/ajmga61544.pd

A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study

Background A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD

Methods to discover and validate biofluid-based biomarkers in neurodegenerative dementias

Neurodegenerative dementias are progressive diseases that cause neuronal network breakdown in different brain regions often because of accumulation of misfolded proteins in the brain extracellular matrix, such as amyloids, or inside neurons or other cell types of the brain. Several diagnostic protein biomarkers in body fluids are being used and implemented, such as for Alzheimer's disease. However, there is still a lack of biomarkers for co-pathologies and other causes of dementia. Such biofluid-based biomarkers enable precision medicine approaches for diagnosis and treatment, allow to learn more about underlying disease processes, and facilitate the development of patient inclusion and evaluation tools in clinical trials. When designing studies to discover novel biofluid-based biomarkers, choice of technology is an important starting point. But there are so many technologies to choose among. To address this, we here review the technologies that are currently available in research settings and, in some cases, in clinical laboratory practice. This presents a form of lexicon on each technology addressing its use in research and clinics, its strengths and limitations, and a future perspective

The human secretome

The proteins secreted by human cells (collectively referred to as the secretome) are important not only for the basic understanding of human biology but also for the identification of potential targets for future diagnostics and therapies. Here, we present a comprehensive analysis of proteins predicted to be secreted in human cells, which provides information about their final localization in the human body, including the proteins actively secreted to peripheral blood. The analysis suggests that a large number of the proteins of the secretome are not secreted out of the cell, but instead are retained intracellularly, whereas another large group of proteins were identified that are predicted to be retained locally at the tissue of expression and not secreted into the blood. Proteins detected in the human blood by mass spectrometry-based proteomics and antibody-based immuno-assays are also presented with estimates of their concentrations in the blood. The results are presented in an updated version 19 of the Human Protein Atlas in which each gene encoding a secretome protein is annotated to provide an open-access knowledge resource of the human secretome, including body-wide expression data, spatial localization data down to the single-cell and subcellular levels, and data about the presence of proteins that are detectable in the blood

Thyrotropin—releasing hormone and amphetamine: A comparison of pharmacological profiles in animals

1. 1. The pharmacological effects of TRH are compared to those produced by d-amphetamine in an attempt to elucidate the mechanisms underlying the activity of this endogenous peptide. 2. 2. Although numerous amphetamine-like actions have been attributed to TRH, several differences have been noted between these compounds and are discussed. 3. 3. At present, it is impossible to propose a single mechanism of action to explain the behavioral effects of TRH

Computer Simulation to Determine How Rapid Anesthetic Recovery Protocols to Decrease the Time for Emergence or Increase the Phase I Postanesthesia Care Unit Bypass Rate Affect Staffing of an Ambulatory Surgery Center

Ambulatory surgery centers (ASC) are implementing new anesthetic techniques and rapid recovery protocols in the postanesthesia care unit (PACU) to achieve earlier discharge after general anesthesia.Using computer simulation, we addressed two questions. First, what is the decrease in an ASCʼs operating room (OR) staff if the time from which the surgery is finished to the time the patient leaves the OR is decreased? Second, what is the decrease in PACU nursing staffing if patients bypass phase I PACU (i.e., proceed from the OR directly to the phase II PACU)? The decrease in labor costs from rapid emergence or fast-tracking depends on how staff are compensated, how many ORs routinely run concurrently, and what percentage of patients undergo general anesthesia. The results show potential decreases in ASCsʼ labor costs ($7.39 per case) from technologies (e.g., new anesthetics or Bispectral Index[trade mark sign] [Aspect Medical Systems, Natick, MA] monitoring) to decrease emergence times or increase the phase I bypass rates. ImplicationsDecreases in operating room and postanesthesia care unit labor costs resulting from faster emergence and phase I postanesthesia care unit bypass vary depending on the amount of routine overtime, how the staff are compensated, and how many patients are routinely anesthetized each day.(Anesth Analg 1999;88:1053-63

Neurotensin, a biologically active peptide

Neurotensin, a tridecapeptide appears to be localized in various parts of the brain and gut. A high affinity binding component of neurotensin to brain membranes, synaptosomes and mast cells has been reported. After peripheral administration the peptide exerts a medley of effects which appear directed mainly to glucose metabolism. In addition, complex vascular effects have also been noted including hypotensin, cyanosis, vasodilation and increased permeability. The peptide may also be associated with inflammatory events. Complex effects upon the secretion of anterior pituitary tropic hormones have been observed. After central administration neurotensin exerts several effects all of which appear to be sufficiently explained by the potent hypothermic action. The resolution of the question of which, if any, of the actions of neurotensin are involved in physiological regulation has not been achieved

Centrally administered neurotensin: Activity in the Julou-Courvoisier muscle relaxation test in mice

Intracisternal (IC) neurotensin (NT) produces muscle relaxation in the Julou-Courvoisier traction test, a screening procedure utilized for assessing neuroleptic drug activity. A dose-response relationship was not observed. IC administration of thyrotropin-releasing hormone (TRH) totally abolished the effects of NT. Two other peptides, substance P and bradykinin, were inactive in the traction test. These data provide further evidence for CNS effects of NT and indicate that this peptide exerts neuroleptic-like activity in a screening test for antipsychotic agents