Serum osteoprotegerin is associated with pulse pressure in kidney transplant recipients

Pulse pressure (PP) reflects increased large artery stiffness, which is caused, in part, by arterial calcification in patients with chronic kidney disease. PP has been shown to predict both cardiovascular and cerebrovascular events in various patient populations, including kidney transplant (KTX) recipients. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in hemodialysis patients. Here we tested the hypothesis that OPG is associated with increased pulse pressure. We cross-sectionally analyzed the association between serum OPG and PP in a prevalent cohort of 969 KTX patients (mean age: 51 +/- 13 years, 57% male, 21% diabetics, mean eGFR 51 +/- 20 ml/min/1.73 m2). Independent associations were tested in a linear regression model adjusted for multiple covariables. PP was positively correlated with serum OPG (rho = 0.284, p < 0.001). Additionally, a positive correlation was seen between PP versus age (r = 0.358, p < 0.001), the Charlson Comorbidity Index (r = 0.232, p < 0.001), serum glucose (r = 0.172, p < 0.001), BMI (r = 0.133, p = 0.001) and serum cholesterol (r = 0.094, p = 0.003). PP was negatively correlated with serum Ca, albumin and eGFR. The association between PP and OPG remained significant after adjusting for multiple potentially relevant covariables (beta = 0.143, p < 0.001). We conclude that serum OPG is independently associated with pulse pressure in kidney transplant recipients

CT screened arterial calcification as a risk factor for mortality after trauma

BACKGROUND: Arterial calcification on Computerised Tomography (CT) is a marker of cardiovascular disease. It is predictive of future adverse cardiac events and mortality in many disease states. The incidence of arterial disease and its impact on outcomes of the injured is not known. The objectives of this study were to describe the incidence of arterial calcification in trauma patients, and establish its impact on mortality. METHODS: A retrospective cohort study of all injured patients aged over 45 years presenting to a major trauma centre over a 34-month period. The presence and quantity of coronary, aortic and abdominal arterial calcification on admission CT scans of the chest, abdomen and pelvis was established, and the association between cardiovascular disease and in-hospital mortality following trauma was determined. RESULTS: Five hundred ninety-one patients were included in the study. Cardiac calcium was visible on 432 (73 %) scans, and abdominal arterial calcification on 472 (79.9 %). Fifty (8.5 %) patients died. Patients with Superior Mesenteric (SMA) and Common Iliac Artery calcification had a significantly higher mortality than those without (p < 0.01). In multivariarate analysis, only SMA calcification was independently associated with mortality (OR 2.462, 95 % CI 1.08–5.60, p = 0.032). Coronary calcium demonstrated no independent statistical relationship with death (Left Anterior Descending Artery OR 1.189, 95 % CI 0.51–2.78, Circumflex OR 1.290, 95 % CI 0.56–2.98, Right Coronary Artery OR 0.483, 95 % CI 0.21–1.10). DISCUSSION: This study has demonstrated that the identification of arterial calcification on admission CT scans of trauma patients is possible. Calcification was common, and present in around three-quarters of injured individuals over the age of 45 years. SMA calcium was an independent predictor of mortality. However, whilst the presence of arterial calcium demonstrated a tendency towards lower survival, this association was not significant in other territories, including the coronary arteries. Future studies should investigate further the association and pathophysiology linking SMA disease and mortality in trauma, in addition to the relationship between longer tem survival, adverse cardiac events and arterial calcification in injured patients. CONCLUSIONS: Arterial calcification can be reliably identified on trauma CT scans, and is common in injured patients. Abdominal vascular calcification appears to be a better predictor of mortality than coronary artery disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13049-016-0317-1) contains supplementary material, which is available to authorized users

Use of fluorescence imaging and indocyanine green during colorectal surgery: Results of an intercontinental Delphi survey

BACKGROUND: Fluorescence imaging with indocyanine green is increasingly being used in colorectal surgery to assess anastomotic perfusion, and to detect sentinel lymph nodes. METHODS: In this 2-round, online, Delphi survey, 35 international experts were asked to vote on 69 statements pertaining to patient preparation and contraindications to fluorescence imaging during colorectal surgery, indications, technical aspects, potential advantages/disadvantages, and effectiveness versus limitations, and training and research. Methodological steps were adopted during survey design to minimize risk of bias. RESULTS: More than 70% consensus was reached on 60 of 69 statements, including moderate-strong consensus regarding fluorescence imaging's value assessing anastomotic perfusion and leak risk, but not on its value mapping sentinel nodes. Similarly, although consensus was reached regarding most technical aspects of its use assessing anastomoses, little consensus was achieved for lymph-node assessments. Evaluating anastomoses, experts agreed that the optimum total indocyanine green dose and timing are 5 to 10 mg and 30 to 60 seconds pre-evaluation, indocyanine green should be dosed milligram/kilogram, lines should be flushed with saline, and indocyanine green can be readministered if bright perfusion is not achieved, although how long surgeons should wait remains unknown. The only consensus achieved for lymph-node assessments was that 2 to 4 injection points are needed. Ninety-six percent and 100% consensus were reached that fluorescence imaging will increase in practice and research over the next decade, respectively. CONCLUSION: Although further research remains necessary, fluorescence imaging appears to have value assessing anastomotic perfusion, but its value for lymph-node mapping remains questionable

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications

In Vivo Generation of Neurotoxic Prion Protein: Role for Hsp70 in Accumulation of Misfolded Isoforms

Prion diseases are incurable neurodegenerative disorders in which the normal cellular prion protein (PrPC) converts into a misfolded isoform (PrPSc) with unique biochemical and structural properties that correlate with disease. In humans, prion disorders, such as Creutzfeldt-Jakob disease, present typically with a sporadic origin, where unknown mechanisms lead to the spontaneous misfolding and deposition of wild type PrP. To shed light on how wild-type PrP undergoes conformational changes and which are the cellular components involved in this process, we analyzed the dynamics of wild-type PrP from hamster in transgenic flies. In young flies, PrP demonstrates properties of the benign PrPC; in older flies, PrP misfolds, acquires biochemical and structural properties of PrPSc, and induces spongiform degeneration of brain neurons. Aged flies accumulate insoluble PrP that resists high concentrations of denaturing agents and contains PrPSc-specific conformational epitopes. In contrast to PrPSc from mammals, PrP is proteinase-sensitive in flies. Thus, wild-type PrP rapidly converts in vivo into a neurotoxic, protease-sensitive isoform distinct from prototypical PrPSc. Next, we investigated the role of molecular chaperones in PrP misfolding in vivo. Remarkably, Hsp70 prevents the accumulation of PrPSc-like conformers and protects against PrP-dependent neurodegeneration. This protective activity involves the direct interaction between Hsp70 and PrP, which may occur in active membrane microdomains such as lipid rafts, where we detected Hsp70. These results highlight the ability of wild-type PrP to spontaneously convert in vivo into a protease-sensitive isoform that is neurotoxic, supporting the idea that protease-resistant PrPSc is not required for pathology. Moreover, we identify a new role for Hsp70 in the accumulation of misfolded PrP. Overall, we provide new insight into the mechanisms of spontaneous accumulation of neurotoxic PrP and uncover the potential therapeutic role of Hsp70 in treating these devastating disorders

Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications

Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: a literature review

Purpose: Given that the relationship between vitamin D status and metabolic diseases such as obesity and type 2 diabetes (T2D) remains unclear, this review will focus on the genetic associations, which are less prone to confounding, between vitamin D-related single nucleotide polymorphisms (SNPs) and metabolic diseases. Methods: A literature search of relevant articles was performed on PubMed up to December 2019. Those articles that had examined the association of vitamin D-related SNPs with obesity and/or T2D were included. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. In total, 73 articles were included in this review. Results: There is a lack of research focussing on the association of vitamin D synthesis-related genes with obesity and T2D; however, the limited available research, although inconsistent, is suggestive of a protective effect on T2D risk. While there are several studies that investigated the vitamin D metabolism-related SNPs, the research focussing on vitamin D activation, catabolism and transport genes is limited. Studies on CYP27B1, CYP24A1 and GC genes demonstrated a lack of association with obesity and T2D in Europeans; however, significant associations with T2D were found in South Asians. VDR gene SNPs have been extensively researched; in particular, the focus has been mainly on BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and FokI (rs2228570) SNPs. Even though the association between VDR SNPs and metabolic diseases remain inconsistent, some positive associations showing potential effects on obesity and T2D in specific ethnic groups were identified. Conclusion: Overall, this literature review suggests that ethnic-specific genetic associations are involved. Further research utilizing large studies is necessary to better understand these ethnic-specific genetic associations between vitamin D deficiency and metabolic diseases