Turbulent flow as a cause for underestimating coronary flow reserve measured by Doppler guide wire

BACKGROUND: Doppler-tipped coronary guide-wires (FW) are well-established tools in interventional cardiology to quantitatively analyze coronary blood flow. Doppler wires are used to measure the coronary flow velocity reserve (CFVR). The CFVR remains reduced in some patients despite anatomically successful coronary angioplasty. It was the aim of our study to test the influence of changes in flow profile on the validity of intra-coronary Doppler flow velocity measurements in vitro. It is still unclear whether turbulent flow in coronary arteries is of importance for physiologic studies in vivo. METHODS: We perfused glass pipes of defined inner diameters (1.5 – 5.5 mm) with heparinized blood in a pulsatile flow model. Laminar and turbulent flow profiles were achieved by varying the flow velocity. The average peak velocity (APV) was recorded using 0.014 inch FW. Flow velocity measurements were also performed in 75 patients during coronary angiography. Coronary hyperemia was induced by intra-coronary injection of adenosine. The APV maximum was taken for further analysis. The mean luminal diameter of the coronary artery at the region of flow velocity measurement was calculated by quantitative angiography in two orthogonal planes. RESULTS: In vitro, the measured APV multiplied with the luminal area revealed a significant correlation to the given perfusion volumes in all diameters under laminar flow conditions (r(2 )> 0.85). Above a critical Reynolds number of 500 – indicating turbulent flow – the volume calculation derived by FW velocity measurement underestimated the actual rate of perfusion by up to 22.5 % (13 ± 4.6 %). In vivo, the hyperemic APV was measured irrespectively of the inherent deviation towards lower velocities. In 15 of 75 patients (20%) the maximum APV exceeded the velocity of the critical Reynolds number determined by the in vitro experiments. CONCLUSION: Doppler guide wires are a valid tool for exact measurement of coronary flow velocity below a critical Reynolds number of 500. Reaching a coronary flow velocity above the velocity of the critical Reynolds number may result in an underestimation of the CFVR caused by turbulent flow. This underestimation of the flow velocity may reach up to 22.5 % compared to the actual volumetric flow. Cardiologists should consider this phenomena in at least 20 % of patients when measuring CFVR for clinical decision making

Fatal Injuries in the Slums of Nairobi and their Risk Factors: Results from a Matched Case-Control Study

Injuries contribute significantly to the rising morbidity and mortality attributable to non-communicable diseases in the developing world. Unfortunately, active injury surveillance is lacking in many developing countries, including Kenya. This study aims to describe and identify causes of and risk factors for fatal injuries in two slums in Nairobi city using a demographic surveillance system framework. The causes of death are determined using verbal autopsies. We used a nested case-control study design with all deaths from injuries between 2003 and 2005 as cases. Two controls were randomly selected from the non-injury deaths over the same period and individually matched to each case on age and sex. We used conditional logistic regression modeling to identity individual- and community-level factors associated with fatal injuries. Intentional injuries accounted for about 51% and unintentional injuries accounted for 49% of all injuries. Homicides accounted for 91% of intentional injuries and 47% of all injury-related deaths. Firearms (23%) and road traffic crashes (22%) were the leading single causes of deaths due to injuries. About 15% of injuries were due to substance intoxication, particularly alcohol, which in this community comes from illicit brews and is at times contaminated with methanol. Results suggest that in the pervasively unsafe and insecure environment that characterizes the urban slums, ethnicity, residence, and area level factors contribute significantly to the risk of injury-related mortality

Pilot study of losartan for pulmonary hypertension in chronic obstructive pulmonary disease

BACKGROUND: Morbidity in COPD results from a combination of factors including hypoxia-induced pulmonary hypertension, in part due to pulmonary vascular remodelling. Animal studies suggest a role of angiotensin II and acute studies in man concur. Whether chronic angiotensin-II blockade is beneficial is unknown. We studied the effects of an angiotensin-II antagonist losartan, on haemodynamic variables, exercise capacity and symptoms. METHODS: This was a double-blind, randomized, parallel group, placebo- controlled study of 48 weeks duration. Forty patients with COPD and pulmonary hypertension (Tran tricuspid pressure gradient (TTPG) = 30 mmHg) were randomised to losartan 50 mg or placebo. Changes in TTPG were assessed at 3, 6 and 12 months. RESULTS: There was a trend for TTPG to increase in the placebo group (baseline 43.4 versus 48.4 mmHg at endpoint) and stay constant in the losartan group (baseline 42.8 versus 43.6 mmHg). More patients in the losartan group (50%) than in the placebo group (22%) showed a clinically meaningful reduction in TTPG at any timepoint; these effects seemed more marked in patients with higher baseline TTPG. There were no clear improvements in exercise capacity or symptoms. CONCLUSION: In this 12-month pilot study, losartan 50 mg had no statistically significant beneficial effect on TTPG, exercise capacity or symptoms in pulmonary hypertension secondary to obstructive disease. A sub-group of patients with higher TTPG may benefit

Leishmania-Specific Surface Antigens Show Sub-Genus Sequence Variation and Immune Recognition

Single-celled Leishmania parasites, transmitted by sand flies, infect humans and other mammals in many tropical and sub-tropical regions, giving rise to a spectrum of diseases called the leishmaniases. Species of parasite within the Leishmania genus can be divided into two groups (referred to as sub-genera) that are separated by up to 100 million years of evolution yet are highly related at the genome level. Our research is focused on identifying gene differences between these sub-genera that may identify proteins that impact on the transmission and pathogenicity of different Leishmania species. Here we report the presence of a highly-variant genomic locus (OHL) that was previously described as absent in parasites of the L. (Viannia) subgenus (on the basis of lack of key genes) but is present and well-characterised (as the LmcDNA16 locus) in all members of the alternative subgenus, L. (Leishmania). We demonstrate that the proteins encoded within the LmcDNA16 and OHL loci are similar in their structure and surface localisation in mammalian-infective amastigotes, despite significant differences in their DNA sequences. Most importantly, we demonstrate that the OHL locus proteins, like the HASP proteins from the LmcDNA16 locus, contain highly variable amino acid repeats that are antigenic in man and may therefore contribute to future vaccine development

The unique resistance and resilience of the Nigerian West African Dwarf goat to gastrointestinal nematode infections

<p>Abstract</p> <p>Background</p> <p>West African Dwarf (WAD) goats serve an important role in the rural village economy of West Africa, especially among small-holder livestock owners. They have been shown to be trypanotolerant and to resist infections with <it>Haemonchus contortus </it>more effectively than any other known breed of goat.</p> <p>Methods</p> <p>In this paper we review what is known about the origins of this goat breed, explain its economic importance in rural West Africa and review the current status of our knowledge about its ability to resist parasitic infections.</p> <p>Conclusions</p> <p>We suggest that its unique capacity to show both trypanotolerance and resistance to gastrointestinal (GI) nematode infections is immunologically based and genetically endowed, and that knowledge of the underlying genes could be exploited to improve the capacity of more productive wool and milk producing, but GI nematode susceptible, breeds of goats to resist infection, without recourse to anthelmintics. Either conventional breeding allowing introgression of resistance alleles into susceptible breeds, or transgenesis could be exploited for this purpose. Appropriate legal protection of the resistance alleles of WAD goats might provide a much needed source of revenue for the countries in West Africa where the WAD goats exist and where currently living standards among rural populations are among the lowest in the world.</p

Human male gamete endocrinology: 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates different aspects of human sperm biology and metabolism

<p>Abstract</p> <p>Background</p> <p>A wider biological role of 1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D3, in tissues not primarily related to mineral metabolism was suggested. Recently, we evidenced the ultrastructural localization the 1,25(OH)2D3 receptor in the human sperm. However, the 1,25(OH)2D3 action in human male reproduction has not yet been clarified.</p> <p>Methods and Results</p> <p>By RT-PCR, Western blot and Immunofluorescence techniques, we demonstrated that human sperm expresses the 1,25(OH)2D3 receptor (VDR). Besides, 25(OH)D3-1 alpha-hydroxylase, evidenced by Western blot analysis, indicated that in sperm 1,25(OH)2D3 is locally produced, highlighting the potential for autocrine-paracrine responses. 1,25(OH)2D3 through VDR, increased intracellular Ca2+ levels, motility and acrosin activity revealing an unexpected significance of this hormone in the acquisition of fertilizing ability. In sperm, 1,25(OH)2D3 through VDR, reduces triglycerides content concomitantly to the increase of lipase activity. Rapid responses stimulated by 1,25(OH)2D3 have been observed on Akt, MAPK and GSK3 implying that this secosteroid is involved in different sperm signalling pathways.</p> <p>Conclusion</p> <p>Our data extended the role of 1,25(OH)2D3 beyond its conventional physiological actions, paving the way for novel therapeutic opportunities in the treatment of the male reproduction disorders.</p

Comparative Expression Profiling of Leishmania: Modulation in Gene Expression between Species and in Different Host Genetic Backgrounds

The single-celled parasite Leishmania, transmitted by sand flies in more than 88 tropical and sub-tropical countries globally, infects man and other mammals, causing a spectrum of diseases called the leishmaniases. Over 12 million people are currently infected worldwide with 2 million new cases reported each year. The type of leishmaniasis that develops in the mammalian host is dependent on the species of infecting parasite and the immune response to infection (that can be influenced by host genetic variation). Our research is focused on identifying parasite factors that contribute to pathogenicity in the host and understanding how these might differ between parasite species that give rise to the different clinical forms of leishmaniasis. Molecules of this type might lead to new therapeutic tools in the longer term. In this paper, we report a comparative analysis of gene expression profiles in three Leishmania species that give rise to different types of disease, focusing on the intracellular stages that reside in mammalian macrophages. Our results show that there are only a small number of differences between these parasite species, with host genetics playing only a minor role in influencing the parasites' response to their intracellular habitat. These small changes may be significant, however, in determining the clinical outcome of infection

‘‘Beet-ing’’ the Mountain: A Review of the Physiological and Performance Effects of Dietary Nitrate Supplementation at Simulated and Terrestrial Altitude

Exposure to altitude results in multiple physiological consequences. These include, but are not limited to, a reduced maximal oxygen consumption, drop in arterial oxygen saturation, and increase in muscle metabolic perturbations at a fixed sub-maximal work rate. Exercise capacity during fixed work rate or incremental exercise and time-trial performance are also impaired at altitude relative to sea-level. Recently, dietary nitrate (NO3-) supplementation has attracted considerable interest as a nutritional aid during altitude exposure. In this review, we summarise and critically evaluate the physiological and performance effects of dietary NO3- supplementation during exposure to simulated and terrestrial altitude. Previous investigations at simulated altitude indicate that NO3- supplementation may reduce the oxygen cost of exercise, elevate arterial and tissue oxygen saturation, improve muscle metabolic function, and enhance exercise capacity/ performance. Conversely, current evidence suggests that NO3- supplementation does not augment the training response at simulated altitude. Few studies have evaluated the effects of NO3- at terrestrial altitude. Current evidence indicates potential improvements in endothelial function at terrestrial altitude following NO3- supplementation. No effects of NO3- supplementation have been observed on oxygen consumption or arterial oxygen saturation at terrestrial altitude, although further research is warranted. Limitations of the present body of literature are discussed, and directions for future research are provided

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Tracking SARS-CoV-2 mutations and variants through the COG-UK-Mutation Explorer

COG-UK Mutation Explorer (COG-UK-ME, https://sars2.cvr.gla.ac.uk/cog-uk/—last accessed date 16 March 2022) is a web resource that displays knowledge and analyses on SARS-CoV-2 virus genome mutations and variants circulating in the UK, with a focus on the observed amino acid replacements that have an antigenic role in the context of the human humoral and cellular immune response. This analysis is based on more than 2 million genome sequences (as of March 2022) for UK SARS-CoV-2 data held in the CLIMB-COVID centralised data environment. COG-UK-ME curates these data and displays analyses that are cross-referenced to experimental data collated from the primary literature. The aim is to track mutations of immunological importance that are accumulating in current variants of concern and variants of interest that could alter the neutralising activity of monoclonal antibodies (mAbs), convalescent sera, and vaccines. Changes in epitopes recognised by T cells, including those where reduced T cell binding has been demonstrated, are reported. Mutations that have been shown to confer SARS-CoV-2 resistance to antiviral drugs are also included. Using visualisation tools, COG-UK-ME also allows users to identify the emergence of variants carrying mutations that could decrease the neutralising activity of both mAbs present in therapeutic cocktails, e.g. Ronapreve. COG-UK-ME tracks changes in the frequency of combinations of mutations and brings together the curated literature on the impact of those mutations on various functional aspects of the virus and therapeutics. Given the unpredictable nature of SARS-CoV-2 as exemplified by yet another variant of concern, Omicron, continued surveillance of SARS-CoV-2 remains imperative to monitor virus evolution linked to the efficacy of therapeutics