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Intravenous flucloxacillin is one of the most frequently used high-dose penicillin therapies in hospitalized patients, forming the cornerstone treatment of invasive Staphylococcus aureus infection. Being a nonreabsorbable anion, flucloxacillin has been suggested to cause hypokalaemia, although the frequency and magnitude of this unwanted effect is unknown. In a retrospective cohort, we investigated the incidence and extent of hypokalaemia after initiation of intravenous flucloxacillin or ceftriaxone therapy. In total, 77 patients receiving flucloxacillin (62% male, mean age 70.5 years) and 84 patients receiving ceftriaxone (46% male, mean age 70.8 years) were included. Hypokalaemia occurred significantly more often in patients receiving flucloxacillin than ceftriaxone (42% vs 14%, p < 10 -4 ). Moreover, follow-up potassium levels were significantly lower during flucloxacillin therapy. In general, women were more prone to develop hypokalaemia than men. In conclusion, intravenous flucloxacillin use is associated with a striking incidence of hypokalaemia. Therefore, standardized potassium measurements are necessary., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Patients with osteoporosis often have chronic kidney disease (CKD). CKD is associated with bone and mineral disturbances, renal osteodystrophy, which like osteoporosis leads to a higher risk of fractures. Bisphosphonates are first-line therapy for osteoporosis; however, these are contra-indicated in patients with a GFR <30 ml/min. In this article, we have reviewed the diagnosis and treatment of osteoporosis in moderate to severe renal failure from data of clinical trials. Results have shown that osteoporosis patients and severe CKD with no signs of renal osteodystrophy, oral bisphosphonates (risedronate) seem to be a safe choice. Renal function and PTH should subsequently be monitored strictly. Denosumab, with regularly monitoring of calcium and adequate vitamin D levels or raloxifene are a possible second choice. In any case, one should be certain that there is no adynamic bone before treatment can be started. If there is any doubt, bone biopsies should be taken.

Background: Osteoporosis, a frequent complication of gastrectomy, increases with age, and the average age of gastric cancer patients continues to rise. This study aims to analyze perioperative factors of osteoporosis after radical gastrectomy. Materials and methods: This retrospective cohort study included patients who underwent dual-energy-X-ray absorptiometry after gastrectomy due to gastric cancer between 2016 and 2019 at Seoul Boramae Medical Center. Data were analyzed from before surgery to 12 months after surgery. Statistical analyses identified osteoporosis risk factors among perioperative factors. Results: Among 189 patients, osteoporosis was diagnosed in 72 patients and peaked at 36 months postoperatively (46.3%; 24 out of 54) with the lowest mean T score of -3.34 although Ca and vitamin D supplements were prescribed to 157 patients (83.1%) on average 32.4 months postoperatively. In multivariate analysis, age (P = 0.002; Adjusted OR: 1.059, 95% CI: 1.020–1.098), body weight (P = 0.009; Adjusted OR: 0.950, 95% CI: 0.914–0.987), sex (P = 0.021; Adjusted OR: 2.322, 95% CI: 1.138–4.739), and serum ALP (P = 0.009; Adjusted OR: 1.023, 95% CI: 1.006–1.040) were significant preoperatively. Additionally, age (P = 0.005; Adjusted OR: 1.067, 95% CI: 1.020–1.116), serum Ca (P = 0.046; Adjusted OR: 0.357, 95% CI: 0.130–0.980), Cr (P = 0.003; Adjusted OR: 0.021, 95% CI: 0.002–0.268), and ALP (P = 0.014; Adjusted OR: 1.017, 95% CI: 1.003–1.030) were observed significantly at 12 months postoperatively. Conclusions: 38.1% of patients were diagnosed with osteoporosis after radical gastrectomy, despite Ca and vitamin D supplements. Age, body weight, sex, serum Ca, Cr, and ALP correlated with osteoporosis perioperatively. [ABSTRACT FROM AUTHOR]

Background: A reduced heparan sulphate (HS) expression in the glomerular basement membrane of patients with overt diabetic nephropathy is associated with an increased glomerular heparanase expression. We investigated the possible association of urinary heparanase activity with the development of proteinuria in patients with Type 1 diabetes (T1D), Type 2 diabetes (T2D), or membranous glomerulopathy (MGP) as non-diabetic disease controls., Methods: Heparanase activity, albumin, HS and creatinine were measured in the urine of patients with T1D (n=58) or T2D (n=31), in patients with MGP (n=52) and in healthy controls (n=10). Heparanase messenger RNA (mRNA) expression in leukocytes was determined in a subgroup of patients with T1D (n=19)., Results: Urinary heparanase activity was increased in patients with T1D and T2D, which was more prominent in patients with macroalbuminuria, whereas no activity could be detected in healthy controls. Albuminuria levels were associated with increased urinary heparanase activity in diabetic patients (r=0.20; P<0.05) but not in patients with MGP (r=0.11; P=0.43). A lower urinary heparanase activity was observed in diabetic patients treated with inhibitors of the renin-angiotensin-aldosterone system (RAAS), when compared to diabetic patients treated with other anti-hypertensives. Additionally, urinary heparanase activity was associated with age in T1D and MGP. In MGP, heparanase activity and β2-microglobulin excretion correlated. In patients with T1D, no differences in heparanase mRNA expression in leukocytes could be observed., Conclusions: Urinary heparanase activity is increased in diabetic patients with proteinuria. However, whether increased heparanase activity is a cause or consequence of proteinuria requires additional research.

Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.

Two adult patients with presumed primary hypertension are presented. In the first patient the diagnosis of coarctation of the aorta was straightforward while in the second patient there was a substantial delay in reaching the correct diagnosis. A 32-year-old patient was analysed for hypertension in the outpatient clinic. At physical examination a systolic cardiac murmur was present and leg blood pressure was not measurable. Magnetic resonance imaging angiography showed a severe coarctation of the thoracic aorta with extensive distended collateral blood vessels. A second patient was a 31-year-old man referred with longstanding hypertension and an unsatisfactory blood pressure response to treatment. Previously, a diagnosis of primary hypertension was made. Renal computed tomography angiography excluded renal artery stenosis as a cause of hypertension but disclosed many distended collateral blood vessels in the musculus rectus abdominis and in the upper abdominal area. Leg blood pressure was measured and further analysis revealed a coarctation of the aorta. Both patients illustrate and emphasise the importance of leg blood pressure measurement at a first analysis of adult hypertensive patients and should always be performed when hypertension is accompanied by murmurs or weak femoral pulsations.

Blood stream infections caused by Candida glabrata are difficult to manage. We describe a patient who underwent an allogeneic peripheral stem cell transplantation for acute myeloid leukaemia. The patient developed C. glabrata fungaemia that was refractory to liposomal amphotericin B therapy. After changing the therapy to caspofungin, blood cultures became sterile within two days and the patient recovered clinically. The patient died shortly after due to graft-versus-host disease and at autopsy there was no evidence of residual or persistent Candida infection. Caspofungin was effective in liposomal amphotericin-B refractory C. glabrata fungaemia and proved to rapidly clear the infection. Treatment options for candidaemia are discussed.

Introduction: Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function., Aims: As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR)., Methods: In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p-aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography., Results: GFR (121 +/- 21 resp. 104 +/- 14 ml/min; P < 0.001) and ERPF (563 +/- 127 resp. 516 +/- 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 +/- 4.5 resp. 13.4 +/- 7 micromol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = -0.43, P < 0.001; control subjects: r = -0.39, P = 0.01)., Conclusion: GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR.

Rationale: L-NMMA is widely used in venous occlusion plethysmography studies to determine baseline NO production. Studies using L-NMMA indicate that endothelial dysfunction is present early in the course of diabetic microvascular complications. However, the optimal dose to maximally inhibit NO-production is unknown., Objective: To determine the L-NMMA-dose that maximally reduces basal forearm blood flow (FBF). To investigate whether there are any differences in the response to L-NMMA between non-complicated type 1 diabetes patients and control subjects., Methods: In eight non-complicated type 1 diabetes patients and nine healthy subjects FBF-responses to intra-arterial infusion of increasing doses of L-NMMA (0.01-1.6 mg/min/dL forearm volume [FAV]) were measured using the perfused forearm technique., Results: Infusion of 0.8 mg/min/dL maximally reduced FBF. The dose of 1.6 mg/min/dL did not additionally reduce FBF. No differences existed between non-complicated type 1 diabetes patients and controls with regard to EC50 (0.017 +/- 0.02 resp. 0.22 +/- 0.02 mg L-NMMA/min/dL) or maximal vasoconstrictive response (Delta FBF: 1.13 +/- 0.4 resp. 0.97 +/- 0.4 mL/min/dL). Throughout the study blood pressure increased significantly in both groups, possibly reflecting a systemic vasoconstrictive effect of L-NMMA., Conclusions: The maximal vasoconstrictive dose was 0.8 mg/min/dL in type 1 diabetes patients as well as the control subjects. There were no significant differences between non-complicated type 1 diabetes subjects and controls with regard to the pharmacodynamics of L-NMMA. At high dosages of L-NMMA a systemic effect can not be ruled out.

A 75-year-old woman presented with angina pectoris and dyspnoea due to critical stenosis of the left main coronary artery with diffuse subendocardial ischaemia.

Type 1 diabetes is a T-cell-mediated chronic disease characterized by the autoimmune destruction of pancreatic insulin-producing beta cells and complete insulin deficiency. It is the result of a complex interrelation of genetic and environmental factors, most of which have yet to be identified. Simultaneous identification of these genetic factors, through use of unphased genotype data, has received increasing attention in the past few years. Several approaches have been described, such as the modified transmission/disequilibrium test procedure, the conditional extended transmission/disequilibrium test, and the stepwise logistic-regression procedure. These approaches are limited either by being restricted to family data or by ignoring so-called "haplotype interactions" between alleles. To overcome this limit, the present study provides a general method to identify, on the basis of unphased genotype data, the haplotype blocks that interact to define the risk for a complex disease. The principle underpinning the proposal is minimal entropy. The performance of our procedure is illustrated for both simulated and real data. In particular, for a set of Dutch type 1 diabetes data, our procedure suggests some novel evidence of the interactions between and within haplotype blocks that are across chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 15, 16, 17, 19, and 21. The results demonstrate that, by considering interactions between potential disease haplotype blocks, we may succeed in identifying disease-predisposing genetic variants that might otherwise have remained undetected.

Background: Previously we observed that atrial natriuretic peptide (ANP)-induced albuminuria was accompanied by an increase in urinary excretion of the low-molecular weight protein (LMW protein) beta2-microglobulin (beta2-m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel (Hoechst, Behring-Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel or Gelofusine (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel on proteinuria. In addition, we have reassessed the effects of ANP., Materials and Methods: We measured urinary beta2-microglobulin (beta2-m) and albumin excretion in healthy volunteers after infusion of a high-dose pure Haemaccel (0.04 mL kg(-1) min(-1) for 60 min), a low-dose Haemaccel (0.01 mL kg(-1) min(-1) for 60 min followed by infusion of 0.02 mL kg(-1) min(-1) for 60 min) and a low-dose Gelofusine (dose comparable to the low-dose Haemaccel). In addition we performed similar studies using ANP dissolved in saline and Haemaccel., Results: Infusion of Haemaccel caused a dose-dependent increase in urinary excretion of beta2-m. There were no differences between Haemaccel and Gelofusine. After infusion of ANP dissolved in Haemaccel urinary beta2-m excretion increased from 0.05 +/- 0.03 microg min(-1) to 27 +/- 10 microg min(-1) and urinary albumin excretion increased from 4.5 +/- 1.1 microg min(-1) to 9.7 +/- 6.3 microg min(-1) (P<0.05). During ANP + saline infusion, urinary beta2-m excretion did not change, whereas the urinary albumin excretion increased from 5.3 +/- 1.5 microg min(-1) to 7.9 +/- 2.4 microg min(-1) (P<0.05)., Conclusions: Our study demonstrates that even low doses of the polygelines Haemaccel and Gelofusine profoundly attenuate the tubular reabsorption of the low-molecular weight protein beta2-m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.

Rationale: The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease., Objective: To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery during venous occlusion plethysmography., Methods: In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of L-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed., Results: Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of L-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups., Conclusions: The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.

In 3 patients, 2 women aged 16 and 64 years and 1 man aged 64 years, with pain in the left hip region and fever, the diagnosis psoas abscess was made. After antibiotic treatment and drainage they recovered well. The primary from of psoas abscess is presumably caused by haematogenous spread of bacteria, mostly Staphylococcus aureus. The secondary form is caused by spread of infection from surrounding tissue, mostly gastrointestinal micro-organisms with Crohn's disease and diverticulitis. Painful passive extension and endorotation as well as a painful flexion stress-test of the hip joint can indicate a psoas abscess. Echography and blood cultures should be performed if a psoas abscess is suspected. If echography is inconclusive, CT-scan can establish the diagnosis. The psoas abscess should be treated by percutaneous or surgical drainage combined with antibiotic therapy. The underlying cause of a secondary psoas abscess should be treated separately.

Parkinson's disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.

There is increasing evidence for the involvement of blood–brain barrier (BBB) in vascular dementia (VaD) and Alzheimer´s disease (AD) pathogenesis. However, the role of endothelial function-related genes in these disorders remains unclear. We evaluated the association of four single-nucleotide polymorphisms (VEGF, VEGFR2 and NOS3) with diagnosis and rate of cognitive decline in AD and VaD in a Spanish case–control cohort (150 VaD, 147 AD and 150 controls). Participants carrying -604AA genotype in VEGFR2 (rs2071559) were less susceptible to VaD after multiple testing. Further analysis for VaD subtype revealed a significant difference between small-vessel VaD patients and controls, but not for large-vessel VaD patients. In addition, -2578A and -460C alleles in VEGF (rs699947 and rs833061) showed to decrease the risk of AD, whereas NOS3 (rs1799983) influenced disease progression. Our study supports previous findings of a deleterious effect of VEGFR2 reduced expression on small-vessel disease, but not on large-vessel disease; as well as a detrimental effect of down-regulating VEGF and eNOS in AD, affecting vascular permeability and neuronal survival. These data highlight the relevance of endothelial function and, therefore, BBB in both VaD and AD. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, but its pathogenesis is still poorly understood. Catheter ablation is one of the most effective treatments for AF, but recurrence after ablation remains a challenge. There has been much research into the association of AF recurrence with several factors, including genetics. Over the past decade or so, significant advances have been made in the genetic architecture of atrial fibrillation. Genome-wide association studies (GWAS) have identified over 100 loci for genetic variants associated with atrial fibrillation. However, there is relatively little information on the systematic assessment of the genes related to AF recurrence after ablation. In this review article, we highlight the value of genetic polymorphisms in atrial fibrillation recurrence after catheter ablation and their potential mechanisms in the recurrence process to enhance our understanding of atrial fibrillation recurrence and contribute to individualized treatment strategies for patients with AF. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) a potent vasodilator synthesized by endothelial cells has anti-atherosclerotic properties and maintains vascular tone. It has been documented that its reduced bioavailability in vascular endothelium plays an important role in the development and progression of coronary artery disease (CAD). Therefore, we aimed to investigate the association of − 786 T > C and 894 G > T polymorphisms of eNOS with CAD. This study included 211 CAD patients and 260 controls of North Indian Punjabi population. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). Logistic regression analysis revealed that the TC and CC genotypes of − 786 T > C were significantly associated with the higher risk of CAD (OR: 2.00, p = 0.001: OR: 4.63, p = 0.001, respectively). Similarly, the GT and TT genotypes of 894 G > T were found to be significantly associated with the higher risk of CAD (OR: 1.96, p = 0.001; OR: 4.54, p = 0.005, respectively). Moreover, the recessive model in − 786 T > C (OR: 3.58, p = 0.002) and 894 G > T (OR: 3.62, p = 0.009) polymorphisms provided 3.6-fold increased risk for CAD. Furthermore, the CG, TT, and CT haplotypes were also associated with the increased risk of CAD (OR: 2.1, p = 0.001; OR: 2, p = 0.002; OR: 3.1, p = 0.001, respectively). In addition, the CC genotype of − 786 T > C and GT genotype of 894 G > T were significantly associated with higher levels of triglycerides (TG) and very low-density lipoproteins cholesterol (VLDL-C). The present study reported the association of − 786 T > C and 894 G > T polymorphisms of eNOS with CAD and abnormal lipid levels in North Indian Punjabi population. [ABSTRACT FROM AUTHOR]

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis. Conclusions: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. What is Known: • Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life. • The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. What is New: • Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis. • We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Polymorphisms of endothelial nitric oxide synthases (eNOS) have been associated with cancer susceptibility. Also, metabolic syndrome is associated with cancer malignancy. However, the effect of eNOS polymorphisms and metabolic syndrome on colorectal cancer (CRC) prognosis remains unclear. Objective: To investigated whether three genetic polymorphisms (− 786 T > C rs2070744, 4a4b rs869109213, and 894G > T rs1799983) in the eNOS and metabolic syndrome (MetS) were associated with CRC patient survival. Methods: We genotyped three polymorphisms of eNOS (− 786 T > C, 4a4b, and 894G > T) in 312 CRC cases from the Korean population by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) analysis. Results: Although the three eNOS polymorphisms were not causative of MetS, the TT genotype of the 894G > T polymorphism was associated with a worse survival rate compared with the GG genotype in the CRC group with MetS than in the CRC group without MetS (5-years survival; adjusted HR = 54.777; 95% CI 5.073–591.487 and RFS; adjusted HR = 14.909; 95% CI 1.571–141.528). Conclusions: The eNOS polymorphisms were not associated with metabolic syndrome prevalence in CRC patients. However, our findings suggest that the eNOS 894G > T polymorphism with MetS was associated with poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Few studies have been conducted to investigate the association of kidney function decline with the trajectories of homocysteine (Hcy) over time, using repeated measurements. We aimed to investigate the association of kidney function with changes in plasma Hcy levels over time. Data were collected from the Rugao Longevity and Ageing Study. In detail, plasma Hcy and creatinine levels were measured in both waves (waves 2, 3 and 4) during the 3·5-year follow-up (n 1135). Wave 2 was regarded as the baseline survey. The estimated glomerular filtration rate (eGFR) was calculated based on creatinine. Subjects were categorised into four groups according to quartiles of eGFR at baseline. Linear mixed-effect models were used to investigate the association of eGFR with subsequent plasma Hcy levels. The mean eGFR at baseline was 90·84 (sd 11·42) ml/min per 1·73 m2. The mean plasma Hcy level was 14·09 (sd 6·82) at baseline and increased to 16·28 (sd 8·27) and 17·36 (sd 10·39) μmol/l during follow-ups. In the crude model, the interaction between time and eGFR at baseline was significant (β = −0·02, 95 % CI −0·02, −0·01, P = 0·002). After adjusting for confounding factors, a significant relationship remained (β = −0·02, 95 % CI −0·02, −0·01, P = 0·003), suggesting that kidney function decline at baseline was associated with a faster increase in Hcy levels. Kidney function decline is associated with a more pronounced increase in plasma Hcy levels. Further studies with longer follow-up periods and larger sample sizes are needed to validate our findings. [ABSTRACT FROM AUTHOR]

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From rat studies, human case reports and cohort studies, bisphosphonates seem to impair renal function. However, when critically reviewing the literature, zoledronate and pamidronate are more frequently involved in renal deterioration than other bisphosphonates. When bisphosphonate nephropathy occurs, zoledronate more frequently induces tubular toxicity whereas pamidronate typically induces focal segmental glomerulosclerosis. Thus, although bisphosphonates are highly effective in preventing complications for patients with osseous metastases and are highly effective in preventing fractures for patients with osteoporosis, renal function should be monitored closely after initiation of these drugs. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a life‐threatening condition caused by a dysregulated host response to infections and is a leading cause of death in hospitalized patients. The present study aimed to elucidate the possible association between sepsis and the tumor necrosis factor (TNF) gene –308G/A (rs1800629) polymorphism, as well as endothelial nitric oxide synthase (eNOS, NOS3) gene –786T/C (rs2070744), 4a/4b (27 bp‐VNTR in intron 4, rs61722009) and 894G/T (Glu298Asp, rs1799983) polymorphisms. Methods: In total, 188 septic adult cases and 188 healthy controls were enrolled. Genomic DNAs from the controls and patients were analyzed by polymerase chain reaction and restriction fragment length polymorphism methods. Results: There were significant associations between the G/G genotype and G allele of the TNF –308G/A (rs1800629) polymorphism in the sepsis group (p < 0.001). The presence of the T/C genotype (p = 0.002) and C allele (p = 0.001) of the –786T/C (rs2070744) was markedly associated with an increased risk of sepsis. However, no significant associations were found with 4a/4b (27 bp‐VNTR in intron 4, rs61722009) and 894G/T (Glu298Asp, rs1799983) polymorphisms. Higher 4bGC and lower 4bTT haplotype frequencies were associated with sepsis. Conclusions: Our results strongly suggest that TNF gene (−308G/A, rs1800629) and NOS3 gene –786T/C (rs2070744) polymorphisms may modify individual susceptibility to sepsis in the Turkish population. [ABSTRACT FROM AUTHOR]

Key points: The presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both.Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, α1‐microglobulin (α1‐m), β2‐microglobulin (β2‐m) and retinol‐binding protein 4 (RBP4) urine concentrations.Our results indicate that the urinary excretion of β2‐m and RBP4 differs from that of albumin and α1‐m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption.The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria.Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease. To clarify the relative contributions of glomerular filtration and tubular uptake to urinary protein excretion, we developed a mathematical model of protein reabsorption in the human proximal tubule (PT) using Michaelis–Menten kinetics and molar urinary protein measurements taken from human Dent1 disease (CLCN5 loss‐of‐function mutation). β2‐Microglobulin (β2‐m) and retinol‐binding protein 4 (RBP4) are normally reabsorbed with 'very high' efficiency uptake kinetics and fractional urinary excretion of 0.025%, whereas albumin and α1‐microglobulin (α1‐m) are reabsorbed by 'high' efficiency uptake kinetics and 50‐fold higher fractional urinary excretion of 1.15%. Our model correctly predicts the urinary β2‐m, RBP4 and α1‐m content in aristolochic acid nephropathy, and elevated β2‐m excretion with increased single nephron glomerular filtration rate (SNGFR) following unilateral‐nephrectomy. We explored how altered endocytic uptake, water reabsorption, SNGFR and glomerular protein filtration affect excretion. Our results help to explain why β2‐m and RBP4 are more sensitive markers of PT dysfunction than albumin or α1‐m, and suggest that reduced PT sodium and water reabsorption in Fanconi syndrome may contribute to proteinuria. Transition of albumin excretion from normal to microalbuminuria, a 5‐fold increase, corresponds to a 3.5‐fold elevation in albumin glomerular filtration, supporting the use of microalbuminuria screening to detect glomerular leak in diabetes. In macroalbuminuria, small albumin permeability changes produce large changes in excretion. However, changes in SNGFR can alter protein excretion, and hyperfiltration with glomerular leak can combine to increase albuminuria. Our model provides a validated quantitative description of the transport processes underlying the protein composition of human urine in normal and pathophysiological states. Key points: The presence of plasma proteins in urine is difficult to interpret quantitatively. It may be a result of impaired glomerular filtration or impaired proximal tubule (PT) reabsorption, or both.Dent1 disease (CLCN5 mutation) abolishes PT protein reabsorption leaving glomerular function intact. Using urine protein measurements from patients with Dent1 disease and normal individuals, we devised a mathematical model that incorporates two PT transport processes with distinct kinetics. This model predicts albumin, α1‐microglobulin (α1‐m), β2‐microglobulin (β2‐m) and retinol‐binding protein 4 (RBP4) urine concentrations.Our results indicate that the urinary excretion of β2‐m and RBP4 differs from that of albumin and α1‐m in their sensitivity to changes in the glomerular filtration rate, glomerular protein leak, tubular protein uptake via endocytosis and PT water reabsorption.The model predicts quantitatively how hyperfiltration and glomerular leak interact to promote albuminuria.Our model should contribute to improved understanding and interpretation of urine protein measurements in renal disease. [ABSTRACT FROM AUTHOR]

Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases. [ABSTRACT FROM AUTHOR]

Objectives: Lung cancer is a disease characterized by uncontrolled cell growth in the lung tissues. The most common causes of lung cancer include smoking, exposure to radon gas, asbestos, environmental pollutants as well as genetic factors. Nitric oxide (NO) has potential mutagenic and carcinogenic activity and may play an important role in lung cancer. Endothelial NO, synthesized from L‐arginine by endothelial NO synthase (eNOS), inhibits apoptosis and promotes angiogenesis and tumor cell proliferation. The aim of the present study was to examine the possible relationship between eNOS gene intron 4 variable number of tandem repeat (VNTR) and exon 7‐G894T (Glu298Asp) polymorphisms and lung cancer risk. Methods: DNA was extracted from peripheral blood leukocytes of 107 lung cancer patients and 100 control subjects. Designated polymorphisms were identified by polymerase chain reaction (PCR) and/or restriction fragment length polymorphism (RFLP). Results: Our study showed that the frequencies of the b/b genotype and b allele of eNOS gene intron 4 VNTR polymorphism were significantly higher in lung cancer patients than in controls (P < 0.05). However, there was no significant association between eNOS gene G894T polymorphism and lung cancer risk (P > 0.05). Conclusion: These results suggest that the presence of the intron 4 VNTR* b allele and b/b genotype may be a genetic risk factor for development of lung cancer. Further larger‐scale studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases, including hypertension, congestive heart failure, myocardial infarction, stroke and atherosclerosis, are common in patients with chronic kidney disease. Aside from the standard biomarkers, measured to determine cardiovascular risk, new ones have emerged: markers of oxidative stress, apoptosis, inflammation, vascular endothelium dysfunction, atherosclerosis, organ calcification and fibrosis. Unfortunately, their utility for routine clinical application remains to be elucidated. A causal relationship between new markers and cardiovascular diseases in patients with chronic kidney disease remains to be established. First of all, there is a lack of large, randomized trials. Moreover, most studies focus on patients with end-stage renal disease as well as on dialysed patients. In such patients, cardiovascular diseases are already present and advanced while early detection of cardiovascular disease risk factor in patients with early-stages of chronic kidney disease would allow more precise prognosis and, as a result, changes in treatment algorithm. In this article, we conduct a comprehensive review of literature for publications relating to cardiovascular risk factors in patients with early-stages of chronic kidney disease. Overall, there are many encouraging advances in detection of cardiovascular risk factors that are making the future more promising for patients suffering from chronic kidney disease. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between single nucleotide polymorphisms (SNPs) in endothelial nitric oxide synthase (eNOS) and interleukin-8 (IL-8) genes and risk of developing bevacizumab-related adverse events in metastatic breast cancer (mBC) patients.Patients and Methods: mBC patients candidate to receive bevacizumab-based chemotherapy were enrolled in this pharmacogenetic study. eNOS c.-813C>T and c.894G>T, and IL-8 c.-251A>T were analyzed by real time PCR on genomic DNA extracted from peripheral blood. Univariate analysis was performed to test the association between each SNP and treatment-related toxicities.Results: Seventy-six mBC patients were enrolled in the present study. Patients carrying the homozygous variant eNOS c.-813TT genotype showed a statistically significant occurrence of any grade proteinuria when compared to CT or CC genotypes (p = 0.004). No significant association of proteinuria with IL-8 SNP or hypertension with selected eNOS and IL-8 SNPs was found.Conclusions: These findings suggest an association between the eNOS c.-813C>T polymorphism and the development of proteinuria in mBC patients receiving a bevacizumab-based chemotherapy. [ABSTRACT FROM AUTHOR]

The risk of essential arterial hypertension was assessed in carriers of the NOS2 gene variants (rs1800482 (-954G>C), rs3730017 (C>T)). In subjects carrying C allele (rs1800482), the risk for essential arterial hypertension developing was higher by 1.7 times (OR=1.712, 95%CI 1.07-2.74), while the presence of T-allele (rs3730017) had a protective effect (OR=0.304, 95%CI 0.192-0.482). In patients with essential arterial hypertension, the presence of the C allele (rs1800482) was associated with a higher content of NO metabolites in the blood plasma. A positive correlation was found between the plasma content of nitrites and nitrates and the level of transcripts of VCAM1, ICAM1 genes in peripheral blood leukocytes. We found the influence of the C allele carriership on the expression VCAM1 and ICAM1 genes in patients with essential hypertension. It was hypothesized that this polymorphic site in the NOS2 gene can be involved in the development of endothelial dysfunction and essential arterial hypertension through modulation of NO level under condition of inflammation. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Labelled Compounds & Radiopharmaceuticals is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Circulating nitric oxide (NO) and lipid levels are closely associated with coronary artery disease (CAD). It is unclear whether the rs1799983 polymorphism in endothelial nitric oxide synthase (NOS3) gene is associated with plasma levels of NO and lipids. This systematic review and meta-analysis (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) aimed to clarify the relationships between the rs1799983 polymorphism and plasma levels of NO and lipids.Methods: Sixteen studies (2702 subjects) and 59 studies (14 148 subjects) were identified for the association analyses for NO and lipids, respectively. Mean difference (MD) and 95% CI were used to estimate the effects of the rs1799983 polymorphism on plasma NO and lipid levels. The primary outcome variable was NO, and the secondary outcomes included triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C).Results: Carriers of the T allele had lower levels of NO (MD -0.27 μmol/L, 95% CI -0.42 to -0.12 μmol/L, p<0.001) and HDL-C (MD -0.07 mmol/L, 95% CI -0.14 to -0.00 mmol/L, p=0.04), and higher levels of TC (MD 0.13 mmol/L, 95% CI 0.06 to 0.20 mmol/L, p<0.001) and LDL-C (MD 0.14 mmol/L, 95% CI 0.05 to 0.22 mmol/L, p=0.002) than the non-carriers. Triglyceride levels were comparable between the genotypes.Conclusion: The association between the NOS3 rs1799983 polymorphism and CAD may be partly mediated by abnormal NO and lipid levels caused by the T allele. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Hypertension (HT), a common age-related disorder, is an important risk factor for cardiovascular disease. This study aims to identify the prevalence of HT in Portuguese centenarians and evaluate whether gene polymorphisms encoding key molecules in blood pressure (BP) regulation are associated with longevity. There were recruited 253 centenarians (100.26 ± 1.98 years) and 268 control subjects (67.51 ± 3.25 years). Hypertension (ESH/ESC2013 and JNC8) and diabetes (WHO) were evaluate. Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and NOS3 were determined. The prevalence of HT among centenarians was 64.4% and the majority (58.9%) were controlled, differing from control group both on frequency (P < 0.001) and on their control (P < 0.001). We found that HT is a risk factor for not achieving longevity (OR 2.531, 95% CI 1.688–3.793, P < 0.001), the same for diabetes (OR 5.669 95% CI 2.966–10.835, P < 0.001), and male gender (OR 2.196, 95% CI 1.493–3.29, P < 0.001). Hypertension, adjusted for gender and diabetes, was independent risk factor anti-longevity (OR 2.007, 95% CI 1320–3.052, P = 0.001). The ACE_D and NOS3_G alleles were more frequent in centenarians compared to controls (P < 0.001, both cases). ACE_II and NOS3_TT genotypes, adjusted for BP, gender and diabetes, increased risk in 3.748 (95% CI 1.887–7.444) and 2.533 (95% CI 1.483–4.327), respectively, in relation to ACE_DD (P < 0.001) and NOS3_GG (P = 0.001), against longevity. Our findings suggest that the prevalence of hypertension was lower in Portuguese centenarians than in the elderly, reinforcing the importance of better cardiovascular risk profiles to achieve longevity even in the presence of genetic condition. [ABSTRACT FROM AUTHOR]

Based on successful targeting to the αvβ3 integrin of cyclic arginine-glycine-aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin-eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage. [ABSTRACT FROM AUTHOR]

Copyright of Istanbul Medical Journal is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Key events that occur during inflammation include the recruitment, adhesion, and transmigration of leukocytes from the circulation to the site of inflammation. These events are modulated by chemokines, integrins, and selectins and the interaction of these molecules with glycosaminoglycans, predominantly heparan sulfate (HS). The development of HS/heparin mimetics that interfere or inhibit the interactions that occur between glycosaminoglycans and modulators of inflammation holds great potential for use as anti-inflammatory therapeutics. This review will detail the role of HS in the events that occur during inflammation, their interaction and modulation of inflammatory mediators, and the current advances in the development of HS/heparin mimetics as anti-inflammatory biotherapeutics. [ABSTRACT FROM AUTHOR]

In the last 10 years, homocysteine has been regarded as a marker of cardiovascular disease and a definite risk factor for many other diseases. Homocysteine is biosynthesized from methionine through multiple steps and then goes through one of two major metabolic pathways: remethylation and transsulfuration. Hyperhomocysteinemia is a state in which too much homocysteine is present in the body. The main cause of hyperhomocysteinemia is a dysfunction of enzymes and cofactors associated with the process of homocysteine biosynthesis. Other causes include excessive methionine intake, certain diseases and side effects of some drugs. Hyperhomocysteinemia is a trigger for many diseases, such as atherosclerosis, congestive heart failure, age-related macular degeneration, Alzheimer’s disease and hearing loss. There are many studies showing a positive relationship between homocysteine level and various symptoms. We speculate that a high level of homocysteine can be the sole reason or an aggravating factor in numerous diseases for which causal links are not fully understood. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is one of the most severe and unpredictable complications of prematurity. There are two possible mechanisms involved in the pathogenesis of NEC: individual inflammatory response and impaired blood flow in mesenteric vessels with secondary ischemia of the intestine. The aim of this study was to evaluate the possible relationship between polymorphisms: Il-1β 3953C>T, Il-6 −174G>C and −596G>A, TNFα −308G>A, and 86 bp variable number tandem repeat polymorphism of interleukin-1 receptor antagonist (Il-1RN VNTR 86 bp) and three polymorphisms that may participate in arteries tension regulation and in consequence in intestine blood flow impairment: eNOS (894G>T and −786T>C) and END-1 (5665G>T) and NEC in 100 infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. In study population, 22 (22%) newborns developed NEC. Surgery-requiring NEC was present in 7 children. Statistical analysis showed 20-fold higher prevalence of NEC in infants with the genotype TT [OR 20 (3.71–208.7); p = 0.0004] of eNOS 894G>T gene polymorphism. There was a higher prevalence of allele C carriers of eNOS 786T>C in patients with surgery-requiring NEC [OR 4.881 (1.33–21.99); p = 0.013]. Our investigation did not confirm any significant prevalence for NEC development in another studied genotypes/alleles. This study confirms the significant role of polymorphisms that play role in intestine blood flow. Identifying gene variants that increase the risk for NEC development may be useful in screening infants with inherent vulnerability and creating strategies for individualized care. [ABSTRACT FROM AUTHOR]

Abstract: Although coarctation of the aorta (CoAo) is a congenital anomaly, it can pose a diagnostic challenge in those presenting beyond neonatal period, as some patients can remain asymptomatic until complications of hypertension develop later in life. Careful physical examination can play an important role in timely diagnosis and prevention of complications.We present 2 cases of adolescents with undiagnosed CoAo who both presented with nonspecific headaches and hypertension. Both were initially misdiagnosed as essential hypertension until careful detailed physical examination later detected weak/absent femoral pulses and discrepancy in upper and lower limb blood pressures. These findings raised the clinical suspicion of CoAo, which was confirmed on further investigations.Our cases highlight the importance of considering CoAo in the differential diagnosis of hypertension in adolescents. These cases also stress the significance of detailed cardiac examination including 4-limb blood pressure and femoral pulses in a patient presenting to the emergency department with high blood pressure irrespective of the primary complaint., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background and aims: The aim of this study was to explore potential associations of the intron 4 variable number of tandem repeats (VNTR) and E298A polymorphisms of the endothelial nitric oxide synthase (eNOS) gene with slow coronary flow (SCF). The association between plasma nitrate and nitrite (NOx) concentrations and eNOS gene polymorphisms was also assessed. Materials and methods: The intron 4 VNTR and E298A polymorphisms of the eNOS gene were evaluated in the isolated DNA blood samples obtained from the SCF patient group (n = 30) and healthy group consisted of age- and sex-matched controls (n = 61). Results: Plasma NOx level was significantly lower in patients with SCF than in controls. In addition, patients with SCF have significantly lower nitric oxide levels than control subjects within each genotype variants. The allele and genotyped frequencies of the eNOS intron 4 VNTR and E298A polymorphisms were similar between patients with SCF and the controls. Plasma NOx concentrations with respect to the relevant genotypes were found insignificant. Discussion and conclusion: Plasma NOx is lower in patients with SCF than in healthy subjects. Our findings may suggest the lack of association between intron 4 VNTR and E298A polymorphisms of the eNOS gene and SCF. [ABSTRACT FROM AUTHOR]