Co-existence of Phenylketonuria and Fabry disease on a 3 year-old boy: case report

Background: The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU) is an inborn error of the metabolism resulting from a phenylalanine hydroxylase defi ciency. Fabry disease (FD) is an X-linked lysosomal storage disorder due to a defi ciency of the enzyme alpha-galactosidase A. Case presentation: We report a case of a 3-year-old boy affected by classic PKU and FD, both confi rmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specifi c GI symptoms (severe abdominal pain and periodically appearance of not specifi c episodes of gastroenteritis) apparently non related to PKU. Conclusion: This is the fi rst report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of these diseases made very diffi cult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specifi c gastroenteritis episodes. Furthermore, this case report helps to defi ne the early clinical phenotype of FD

Association between KLF6 rs3750861 polymorphism and plasma ceramide concentrations in post-menopausal women with type 2 diabetes

Background and aim: Based on the emerging role of Kruppel-like factor 6 (KLF6) in lipid metabolism, we examined whether there is a relationship between the KLF6 rs3750861 genetic variant and plasma ceramide levels in people with type 2 diabetes mellitus (T2DM). Methods and result: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)] amongst 101 Caucasian post-menopausal women with T2DM, who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramides were measured by targeted liquid chromatography-tandem mass spectrometry assay. Genotyping of the KLF6 rs3750861 polymorphism was performed by TaqMan-Based RT-PCR system. Overall, 87 (86.1%) patients had KLF6 rs3750861 C/C genotype and 14 (13.9%) had C/T or T/T genotypes. After adjustment for age, diabetes-related variables, use of lipid-lowering drugs and other potential confounders, patients with C/T or T/T genotypes had higher plasma Cer(d18:1/18:0) (0.159 ± 0.05 vs. 0.120 ± 0.04 μmol/L, p = 0.012), Cer(d18:1/20:0) (0.129 ± 0.04 vs. 0.098 ± 0.03 μmol/L, p = 0.008), and Cer(d18:1/24:1) (1.236 ± 0.38 vs. 0.978 ± 0.36 μmol/L, p = 0.032) compared with those with C/C genotype. Conclusions: The C/T or T/T genotypes of rs3750861 in the KLF6 gene were closely associated with higher levels of specific plasma ceramides in post-menopausal women with T2DM

Prognostic Impact of Diabetes on Long-term Survival Outcomes in Patients With Heart Failure: A Meta-analysis

OBJECTIVE Several studies have explored the impact of diabetes on mortality in patients with heart failure (HF). However, the extent to which diabetes may confer risk of mortality and hospitalization in this patient population remains imperfectly known. Here we examine the independent prognostic impact of diabetes on the long-term risk of mortality and hospitalization in patients with HF. RESEARCH DESIGN AND METHODS: PubMed, Scopus, and Web of Science from January 1990 to October 2016 were the data sources used. We included large (n >1,000) observational registries and randomized controlled trials with a follow-up duration of at least 1 year. Eligible studies were selected according to predefined keywords and clinical outcomes. Data from selected studies were extracted, and meta-analysis was performed using randomeffects modeling. RESULTS: A total of 31 registries and 12 clinical trials with 381,725 patients with acute and chronic HF and 102,036 all-cause deaths over a median follow-up of 3 years were included in the final analysis. Diabetes was associated with a higher risk of all-cause death (random-effects hazard ratio [HR] 1.28 [95% CI 1.21, 1.35]), cardiovascular death (1.34 [1.20, 1.49]), hospitalization (1.35 [1.20, 1.50]), and the combined end point of all-cause death or hospitalization (1.41 [1.29, 1.53]). The impact of diabetes on mortality and hospitalization was greater in patients with chronic HF than in those with acute HF. Limitations included high heterogeneity and varying degrees of confounder adjustment across individual studies. CONCLUSIONS: This updated meta-analysis shows that the presence of diabetes per se adversely affects long-term survival and risk of hospitalization in patients with acute and chronic HF

Association between specific plasma ceramides and high-sensitivity C-reactive protein levels in postmenopausal women with type 2 diabetes

AIM: Emerging evidence suggests that specific plasma ceramides are involved in the pathophysiology of cardiovascular disease (CVD) and other inflammation-associated diseases. However, only scanty information is currently available on the association between distinct plasma ceramides (those associated with increased cardiovascular morbidity and mortality) and plasma high-sensitivity C-reactive protein (hs-CRP) concentrations in patients with type 2 diabetes mellitus (T2DM), a group at high risk of developing CVD and other chronic inflammation-related conditions. METHODS: Previously, six high-risk plasma ceramide species [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), Cer(d18:1/24:1)] were identified in 92 postmenopausal women with T2DM attending a diabetes outpatients service over a 3-month period. Plasma ceramide levels were measured using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. RESULTS: Plasma hs-CRP levels were positively associated with all measured ceramides on univariable linear regression analyses, but only plasma Cer(d18:1/16:0) (standard \u3b2 coefficient: 0.27, P = 0.015), Cer(d18:1/22:0) (standard \u3b2 coefficient: 0.25, P = 0.032) and Cer(d18:1/24:1) (standard \u3b2 coefficient: 0.30, P = 0.007) remained significantly associated with increased plasma hs-CRP levels after adjusting for age, adiposity measures, diabetes duration, HbA1c, insulin resistance, smoking, hypertension, plasma LDL cholesterol, estimated glomerular filtration rate, preexisting ischaemic heart disease and use of lipid-lowering, antihypertensive, antiplatelet or hypoglycaemic drugs. CONCLUSION: In postmenopausal women with T2DM, elevated levels of specific plasma ceramides are associated with higher plasma hs-CRP levels independent of established cardiovascular risk factors, diabetes-related variables and other potential confounding factors

Association between Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes

Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM

ANXA1 mutation analysis in Italian patients with early onset PD

: Recently, a novel pathogenic variant in Annexin A1 protein (c.4G > A, p.Ala2Thr) has been identified in an Iranian consanguineous family with autosomal recessive parkinsonism. The deficiencies of ANXA1 could lead to extracellular SNCA accumulation, defects in intracellular signaling pathways and synaptic plasticity causing parkinsonism. The aim of this study was to identify rare ANXA1 variants in 95 early-onset PD patients from South Italy. Sequencing analysis of ANXA1 gene revealed only 2 synonymous variants in PD patients (rs1050305, rs149033255). Therefore, we conclude that the recently published ANXA1 mutation is not a common cause of EOPD in Southern Italy

Liste des membres de la Société des Américanistes de Paris au 1er janvier 1913.

Liste des membres de la Société des Américanistes de Paris au 1er janvier 1913.. In: Journal de la Société des Américanistes. Tome 10 n°1, 1913. pp. 8-14

Association between decreasing estimated glomerular filtration rate and risk of cardiac conduction defects in patients with Type 2 Diabetes

AimWe aimed to assess the association between decreasing estimated glomerular filtration rate (eGFR) or abnormal albuminuria and the risk of certain cardiac conduction defects in patients with type 2 diabetes mellitus (T2DM).MethodsWe examined a hospital-based sample of 923 patients with T2DM discharged from our Division of Endocrinology over the years 2007–2014. Standard electrocardiograms (ECGs) were performed in all patients. eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, whilst albuminuria was measured by an immuno-nephelometric method on morning spot urine samples.ResultsA total of 253 (27.4%) patients had some type of cardiac conduction defects on standard ECGs (defined as at least one heart block among first-degree atrioventricular block, second-degree block, third-degree block, left bundle branch block, right bundle branch block, left anterior hemi-block or left posterior hemi-block). Prevalence of patients with eGFRCKD-EPI < 30 mL/min/1.73 m2, eGFRCKD-EPI 59–30 mL/min/1.73 m2 or abnormal albuminuria (i.e. urinary albumin-to-creatinine ratio ≥ 30 mg/g) were 7.0%, 29.4% and 41.3%, respectively. After adjustment for known cardiovascular risk factors, diabetes-related variables and potential confounders, there was a significant, graded association between decreasing eGFR values and risk of any cardiac conduction defects [adjusted-odds ratios of 2.05 (95% CI: 1.2–3.5), 2.85 (95% CI: 1.6–5.1) and 3.62 (95% CI: 1.6–8.1) for eGFRCKD-EPI 89–60, eGFRCKD-EPI 59–30 and eGFRCKD-EPI < 30 mL/min/1.73 m2, respectively]. Conversely, abnormal albuminuria was not independently associated with an increased risk of any conduction defects (adjusted-odds ratio: 1.09, 95% CI: 0.7–1.6).ConclusionDecreasing eGFR is independently associated with an increased risk of cardiac conduction defects in hospitalized patients with T2DM

Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis