Sex differences in primary hypertension

Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences

Treatment of Auditory Processing in Noise in Individuals With Mild Aphasia: Pilot Study

Purpose: Listening in noise challenges listeners with auditory comprehension impairments in aphasia. We examined the effects of Trivia Game, a computerized program with questions spoken in increasing levels of background noise with success in the game. Methods: We piloted Trivia Game in four individuals with chronic aphasia and mild auditory comprehension impairments. Participants played Trivia Game for 12 twenty-minute sessions. In addition to the Western Aphasia Battery (WAB), we measured outcomes on Quick Speech in Noise (QSIN), a sentence repetition test, administered in auditory (AUD) and auditory+visual (AV) conditions as signal-to-noise ratio varied from 25 to 0 dB. Results: All four participants showed progress within the game in the noise level attained. Increases in repetition accuracy were seen in two participants for the QSIN AUD condition (average of 5.5 words), and in three participants for QSIN AV (average of 16.5 words). One individual increased performance on the WAB. Conclusions: Use of Trivia Game led to improved auditory processing abilities in all four individuals with aphasia. Greater gains noted in the AV condition over AUD suggest that Trivia Game may facilitate speech-reading skills to support comprehension of speech in situations with background noise

NIH Initiative to Balance Sex of Animals in Preclinical Studies: Generative Questions to Guide Policy, Implementation, and Metrics

In May of 2014, the NIH Director together with the Director of the Office of Research on Women’s Health announced plans to take a multi-dimensional approach to address the over reliance on male cells and animals in preclinical research. The NIH is engaging the scientific community in the development of policies to improve the sex balance in research. The present, past, and future presidents of the Organization for the Study of Sex Differences, in order to encourage thoughtful discussion among scientists, pose a series of questions to generate ideas in three areas: 1. research strategies, 2. educational strategies, and 3. strategies to monitor effectiveness of policies to improve the sex balance in research. By promoting discussion within the scientific community, a consensus will evolve that will move science forward in a productive and effective manner

Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent

<p>Abstract</p> <p>Background</p> <p>Angotensin converting enzyme 2 (ACE2) is a newly discovered monocarboxypeptidase that counteracts the vasoconstrictor effects of angiotensin II (Ang II) by converting Ang II to Ang-(1-7) in the kidney and other tissues.</p> <p>Methods</p> <p>ACE2 activity from renal homogenates was investigated by using the fluorogenic peptide substrate Mca-YVADAPK(Dnp)-OH, where Mca is (7-methoxycoumarin-4-yl)-acetyl and Dnp is 2,4-dinitrophenyl.</p> <p>Results</p> <p>We found that ACE2 activity expressed in relative fluorescence units (RFU) in the MF1 mouse is higher in the male (M) compared to the female (F) kidney [ACE2 (RFU/min/μg protein): M 18.1 ± 1.0 versus F 11.1 ± 0.39; <it>P </it>< 0.0001; <it>n </it>= 6]. Substrate concentration curves revealed that the higher ACE2 activity in the male was due to increased ACE2 enzyme velocity (V_max) rather than increased substrate affinity (K_m). We used the four core genotypes mouse model in which gonadal sex (ovaries versus testes) is separated from the sex chromosome complement enabling comparisons among XX and XY gonadal females and XX and XY gonadal males. Renal ACE2 activity was greater in the male than the female kidney, regardless of the sex chromosome complement [ACE2 (RFU/min/μg protein): intact-XX-F, 7.59 ± 0.37; intact-XY-F, 7.43 ± 0.53; intact-XX-M, 12.1 ± 0.62; intact-XY-M, 12.7 ± 1.5; <it>n </it>= 4-6/group; <it>P </it>< 0.0001, F versus M, by two-way ANOVA]. Enzyme activity was increased in gonadectomized (GDX) female mice regardless of the sex chromosome complement whereas no effect of gonadectomy was observed in the males [ACE2 (RFU/min/μg protein): GDX-XX-F, 12.4 ± 1.2; GDX-XY-F, 11.1 ± 0.76; GDX-XX-M, 13.2 ± 0.97; GDX-XY-M, 11.6 ± 0.81; <it>n </it>= 6/group]. 17β-oestradiol (E₂) treatment of GDX mice resulted in ACE2 activity that was only 40% of the activity found in the GDX mice, regardless of their being male or female, and was independent of the sex chromosome complement [ACE2 (RFU/min/μg protein): GDX+E₂-XX-F, 5.56 ± 1.0; GDX+E₂-XY-F, 4.60 ± 0.52; GDX+E₂-XX-M, 5.35 ± 0.70; GDX+E₂-XY-M, 5.12 ± 0.47; <it>n </it>= 6/group].</p> <p>Conclusions</p> <p>Our findings suggest sex differences in renal ACE2 activity in intact mice are due, at least in part, to the presence of E₂in the ovarian hormone milieu and not to the testicular milieu or to differences in sex chromosome dosage (2X versus 1X; 0Y versus 1Y). E₂regulation of renal ACE2 has particular implications for women across their life span since this hormone changes radically during puberty, pregnancy and menopause.</p

Role of the Renin Angiotensin System in Blood Pressure Allostasis-induced by Severe Food Restriction in Female Fischer rats

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1-8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1-8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake

Considering sex as a biological variable in preclinical research

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154390/1/fsb2fj201600781r.pd

Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome

Background & Aims: Poorly digested, fermentable carbohydrates may induce symptoms of irritable bowel syndrome (IBS), via unclear mechanisms. We performed a randomized trial with magnetic resonance imaging (MRI) analysis to investigate correlations between symptoms and changes in small and large bowel contents following oral challenge. Methods: We performed a 3-period crossover study of 29 adult patients with IBS (based on Rome III criteria, with symptoms of abdominal pain or discomfort for at least 2 days/week) and reported bloating. In parallel we performed the same study of 29 healthy individuals (controls). Studies were performed in the United Kingdom from January 2013 through February 2015. On 3 separate occasions (at least 7 days apart), subjects were given a 500 ml drink containing 40 g of carbohydrate (glucose in the first period, fructose in the second, and inulin in the third, in a random order). Levels of breath hydrogen were measured and intestinal content was assessed by MRI before and at various time points after consumption of each drink. Symptoms were determined based on subjects’ responses to the Hospital Anxiety and Depression Scale questionnaire and the Patient Health Questionnaire-15. The primary endpoint was whether participants had a clinically important symptom response during the 300 minutes following consumption of the drink. Results: More patients with IBS reached the pre-defined symptom threshold after intake of inulin (13/29) or fructose (11/29) than glucose (6/29). Symptoms peaked sooner after intake of fructose than inulin. Fructose increased small bowel water content in both patients and controls whereas inulin increased colonic volume and gas in both. Fructose and inulin increased breath hydrogen levels in both groups, compared to glucose; fructose produced an earlier increase than inulin. Controls had lower symptom scores during the period after drink consumption than patients with IBS, despite similar MRI parameters and breath hydrogen responses. In patients who reached the symptom threshold after inulin intake, peak symptom intensity correlated with peak colonic gas (r = 0.57; P<0.05). Changes in MRI features and peak breath hydrogen levels were similar in patients who did and did not reach symptom threshold. Conclusions: Patients with IBS and healthy individuals without IBS (controls) have similar physiological responses following intake of fructose or inulin; patients more frequently report symptoms after inulin than controls. In patients with a response to inulin, symptoms relate to levels of intra-luminal gas, but peak gas levels do not differ significantly between responders, non-responders or controls. This indicates that colonic hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in patients with IBS. Clinicaltrials.gov no: NCT0177685

Role of the renin angiotensin system in blood pressure allostasis-induced by severe food restriction in female Fischer rats.

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1?8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (?30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1?8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake

From insect to man: Photorhabdus sheds light on the emergence of human pathogenicity

Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway