Towards precision medicine for hypertension: a review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach

Mild hyperlipidemia in mice aggravates platelet responsiveness in thrombus formation and exploration of platelet proteome and lipidome.

Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Millions of people worldwide display mildly elevated levels of plasma lipids and cholesterol linked to diet and life-style. While the prothrombotic risk of severe hyperlipidemia has been established, the effects of moderate hyperlipidemia are less clear. Here, we studied platelet activation and arterial thrombus formation in Apoe-/- and Ldlr-/- mice fed a normal chow diet, resulting in mildly increased plasma cholesterol. In blood from both knockout mice, collagen-dependent thrombus and fibrin formation under flow were enhanced. These effects did not increase in severe hyperlipidemic blood from aged mice and upon feeding a high-fat diet (Apoe-/- mice). Bone marrow from wild-type or Ldlr-/- mice was transplanted into irradiated Ldlr-/- recipients. Markedly, thrombus formation was enhanced in blood from chimeric mice, suggesting that the hyperlipidemic environment altered the wild-type platelets, rather than the genetic modification. The platelet proteome revealed high similarity between the three genotypes, without clear indication for a common protein-based gain-of-function. The platelet lipidome revealed an altered lipid profile in mildly hyperlipidemic mice. In conclusion, in Apoe-/- and Ldlr-/- mice, modest elevation in plasma and platelet cholesterol increased platelet responsiveness in thrombus formation and ensuing fibrin formation, resulting in a prothrombotic phenotype

Orthodontic treatment needs in the western region of Saudi Arabia: a research report

BACKGROUND: Evaluation of self perceived and actual need for orthodontic treatment helps in planning orthodontic services and estimating the required resources and man power. In the present study, the perceptive need as evaluated by patients and the actual need to orthodontic treatment, as assessed by orthodontists, were evaluated at two types of dental practices in the city of Jeddah using the Index of Orthodontic Treatment Need (IOTN). METHODS: A consecutive sample of 743 adults seeking orthodontic treatment at two different types of dental practices in Jeddah; King Abdulaziz University, Faculty of Dentistry (KAAU) (Free treatment) and two private dental polyclinics (PDP) (Paid treatment), was examined for orthodontic treatment need using the dental health component (DHC) of the IOTN. The self-perceived need for orthodontic treatment was also determined using the aesthetic component (AC) of the IOTN. The IOTN score and the incidence of each variable were calculated statistically. AC and DHC categories were compared using the Chi-Square and a correlation between them was assessed using Spearman's correlation test. AC and DHC were also compared between the two types of dental practices using the Chi-Square. RESULTS: The results revealed that among the 743 patients studied, 60.6% expressed no or slight need for treatment, 23.3% expressed moderate to borderline need and only16.1% thought they needed orthodontic treatment. Comparing these estimates to professional judgments, only 15.2% conformed to little or no need for treatment, 13.2% were assessed as in borderline need and 71.6% were assessed as in need for treatment (p < 0.001). Spearman's correlation test proved no correlation (r = -.045) between the two components. Comparing the AC and the DHC between the KAAU group and PDP group showed significant differences between the two groups (p < 0.001). CONCLUSION: Patient's perception to orthodontic treatment does not always correlate with professional assessment. The IOTN is a valid screening tool that should be used in orthodontic clinics for better services especially, in health centers that provide free treatment

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement. </p

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement. </p

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement. </p

Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

B lineage cells are critically involved in ANCA-associated vasculitis (AAV), evidenced by alterations in circulating B cell subsets and beneficial clinical effects of rituximab (anti-CD20) therapy. This treatment renders a long-term, peripheral B cell depletion, but allows for the survival of long-lived plasma cells. Therefore, there is an unmet need for more reversible and full B lineage cell targeting approaches. To find potential novel therapeutic targets, RNA sequencing of CD27 + memory B cells of patients with active AAV was performed, revealing an upregulated NF-κB-associated gene signature. NF-κB signaling pathways act downstream of various B cell surface receptors, including the BCR, CD40, BAFFR and TLRs, and are essential for B cell responses. Here we demonstrate that novel pharmacological inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signaling) and inhibitor-of-κB-kinase-β (IKKβ, canonical NF-κB signaling) can effectively inhibit NF-κB signaling in B cells, whereas T cell responses were largely unaffected. Moreover, both inhibitors significantly reduced B cell proliferation, differentiation and production of antibodies, including proteinase-3 (PR3) autoantibodies, in B lineage cells of AAV patients. These findings indicate that targeting NF-κB, particularly NIK, may be an effective, novel B lineage cell targeted therapy for AAV and other autoimmune diseases with prominent B cell involvement. </p

Prediction of persistent shoulder pain in general practice: Comparing clinical consensus from a Delphi procedure with a statistical scoring system

<p>Abstract</p> <p>Background</p> <p>In prognostic research, prediction rules are generally statistically derived. However the composition and performance of these statistical models may strongly depend on the characteristics of the derivation sample. The purpose of this study was to establish consensus among clinicians and experts on key predictors for persistent shoulder pain three months after initial consultation in primary care and assess the predictive performance of a model based on clinical expertise compared to a statistically derived model.</p> <p>Methods</p> <p>A Delphi poll involving 3 rounds of data collection was used to reach consensus among health care professionals involved in the assessment and management of shoulder pain.</p> <p>Results</p> <p>Predictors selected by the expert panel were: symptom duration, pain catastrophizing, symptom history, fear-avoidance beliefs, coexisting neck pain, severity of shoulder disability, multisite pain, age, shoulder pain intensity and illness perceptions. When tested in a sample of 587 primary care patients consulting with shoulder pain the predictive performance of the two prognostic models based on clinical expertise were lower compared to that of a statistically derived model (Area Under the Curve, AUC, expert-based dichotomous predictors 0.656, expert-based continuous predictors 0.679 vs. 0.702 statistical model).</p> <p>Conclusions</p> <p>The three models were different in terms of composition, but all confirmed the prognostic importance of symptom duration, baseline level of shoulder disability and multisite pain. External validation in other populations of shoulder pain patients should confirm whether statistically derived models indeed perform better compared to models based on clinical expertise.</p

Hospitalisation with Infection, Asthma and Allergy in Kawasaki Disease Patients and Their Families: Genealogical Analysis Using Linked Population Data

Background: Kawasaki disease results from an abnormal immunological response to one or more infectious triggers. We hypothesised that heritable differences in immune responses in Kawasaki disease-affected children and their families would result in different epidemiological patterns of other immune-related conditions. We investigated whether hospitalisation for infection and asthma/allergy were different in Kawasaki disease-affected children and their relatives. Methods/Major Findings: We used Western Australian population-linked health data from live births (1970-2006) to compare patterns of hospital admissions in Kawasaki disease cases, age- and sex-matched controls, and their relatives. There were 295 Kawasaki disease cases and 598 age- and sex-matched controls, with 1,636 and 3,780 relatives, respectively. Compared to controls, cases were more likely to have been admitted at least once with an infection (cases, 150 admissions (50.8%) vs controls, 210 admissions (35.1%); odds ratio (OR) = 1.9, 95% confidence interval (CI) 1.4-2.6, P = 7.2×10-6), and with asthma/allergy (cases, 49 admissions (16.6%) vs controls, 42 admissions (7.0%); OR = 2.6, 95% CI 1.7-4.2, P = 1.3×10-5). Cases also had more admissions per person with infection (cases, median 2 admissions, 95% CI 1-5, vs controls, median 1 admission, 95% CI 1-4, P = 1.09×10-5). The risk of admission with infection was higher in the first degree relatives of Kawasaki disease cases compared to those of controls, but the differences were not significant. Conclusion: Differences in the immune phenotype of children who develop Kawasaki disease may influence the severity of other immune-related conditions, with some similar patterns observed in relatives. These data suggest the influence of shared heritable factors in these families