Feasibility Analysis of Ultrasound-Guided Placement of Tunneled Hemodialysis Catheters.

Introduction: Radiographic fluoroscopy is the current standard for placement of tunneled central venous catheters (CVCs) for hemodialysis. Radiographic fluoroscopy requires structural and personnel infrastructure and exposes the patient to ionizing radiation. Here, we investigate the feasibility of solely ultrasound-guided placement of tunneled central venous dialysis catheters (USCVCs). Methods: We evaluated prospectively collected single-center data regarding safety and catheter function of 134 consecutive patients who underwent USCVC implantation between 2020 and 2021. We used the inset guidewire to visualize the position of the catheter tip. In the case of inadequate visibility by ultrasound, we used intracardiac electrocardiography (ECG) recording or agitated saline. A total of 1844 catheter days were assessed. The optimal CVC position was defined as being within the upper right atrium (URA) and middle to deep right atrium. Results: Of the 134 USCVCs, 87% were placed on the right side. The primary success rate for optimal tip position and catheter function was 98%. Of the USCVCs, 97% were placed solely by ultrasound. Regarding positioning, 6% were in the vena cava superior zone, 70% in the URA and 24% in the middle to deep right atrium, resulting in a rate of 94% with optimal positioning. Effective blood flow averaged 292 ± 39 ml/min. There were no immediate procedure-associated complications. Conclusion: Placement of CVC for hemodialysis solely by ultrasound is an effective alternative to fluoroscopy-assisted placement.

An unusual presentation of invasive Fusarium aortitis in a patient who is immunocompromised: A case report.

Fusarium (F.) species are ubiquitous filamentous fungi that may cause various opportunistic infections, especially in patients who are immunocompromised. A rare manifestation of disseminated fusariosis affects the aortic valve and results in invasive aortitis, which poses a significant challenge for clinicians in diagnosis and treatment. Here, we report a case of a patient, aged 54 years, who is immunocompromised, presenting initially with Fusarium keratitis and chorioretinitis in both eyes and a new endovascular aortic mass. Positron emission tomography/computed tomography was performed, suggesting aortitis. Transoesophageal echocardiography and electrocardiogram-guided computed tomography-angiography confirmed a large intraluminal mass in the ascending aorta. The aortic mass and a part of the ascending aorta were resected surgically, and a filamentous fungus with the microscopic features of the genus Fusarium was isolated and later identified molecularly as F. petroliphilum. The course of the treatment was complicated by perioperative cerebral embolization and mesenteric ischemia. These complications could be attributed to a preoperatively existing occlusion of the superior and inferior mesenteric artery and a subtotal stenosis of the celiac trunk. This case report describes a rare manifestation of disseminated fusariosis, frequently characterized by protracted clinical courses with poor prognosis. Fusariosis may manifest at different sites at different times or persist as a long-lasting disease with reactivation. This case highlights the importance of the interdisciplinary approach for effectively treating invasive mycoses.

Efficient stabilization of therapeutic hepatitis B vaccine components by amino-acid formulation maintains its potential to break immune tolerance.

Background & Aims: Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach. Methods: We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice. Results: In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice. Conclusion: SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide. Impact and implications: Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.

[Treatment response and complications of older patients with ANCA(antineutrophil cytoplasmatic antibody)-associated vasculitis]. / Therapieansprechen und Komplikationen von älteren Patienten mit ANCA(antineutrophile cytoplasmatische Antikörper)-assoziierten Vaskulitiden.

BACKGROUND: ANCA (antineutrophil cytoplasmatic antibody)-associated vasculitis (AAV) mainly affects elderley people but adjusted therapy concepts for this patient group are lacking. AIM: The aim of this study was therefore to analyze differences in course and outcome of patients with AAV with respect to age. MATERIALS AND METHODS: 62 patients were analyzed for treatment response, of whom 53 (85%) experienced adverse events (AE and SAE) that could be evaluated. Older (> 65 yrs.) versus younger (< 65 yrs.) patients were compared. Treatment response was assessed at 6 months, complications were assessed over 18 months. RESULTS: Treatment response was not seen to differ by age groups. In multiple logistic regression, pulmonary involvement (OR = 6,9; CI = 1,7-27,8, p < 0,01) and ΔGFR [ml/min] (OR = 0,93; CI = 0,89-0,97, p < 0,01) were predictors of SAE. 14 patients had more than 1 SAE. Again, pulmonary involvement (28,2% vs. 78,6%, p < 0,01) was a risk factor and older patients (78,6% vs. 43,6%, p = 0,025) were more frequently affected. Patients with multiple SAEs received glucocorticoids of more than 5 mg/d for longer periods of time (171 ± 65 days vs. 120 ± 70 days, p = 0,03). DISCUSSION: No differences were found between older and younger patients with regard to treatment response. Multiple SAEs occurred more frequently in elderly patients. There was a correlation between pulmonary manifestation and duration of glucocorticoid therapy with a complicated course. The most frequent SAEs were infections requiring hospitalisation. CONCLUSION: Therapy for elderly patients should be individualized with the goal of a fast reduction of glucocorticoids. Special monitoring is indicated for elderly patients, especially those with pulmonary involvement.

[Frailty in renal diseases]. / "Frailty" bei nephrologischen Erkrankungen.

The term frailty describes a complex syndrome of reduced resistance to stress factors as a consequence of age-related degeneration in various organ systems.In the general population frailty is associated with poor clinical outcomes, including an increased risk of falls, hospitalization, functional impairment and mortality. Frailty occurs earlier and its prevalence is higher in patients with chronic kidney disease (CKD) compared to the general population. Frail patients with CKD, on dialysis or not, have reduced quality of life and increased hospitalization and mortality rates, regardless of age, sex or comorbidities.The identification of frailty in patients with CKD can lead to the detection of important and potentially modifiable risk factors. Early nephrological evaluation coupled with an interdisciplinary approach including primary care physicians, geriatricians, physiotherapists, occupational therapists and nutritionists, is fundamental in the prevention of frailty as well as in the management of frail patients with CKD.Several instruments have been developed to screen for and assess the degree of frailty; however, there is currently no recommendation as to which should be used in nephrology and how to manage frail patients with CKD. In this article we suggest an approach based on a multidimensional, interdisciplinary evaluation aimed at the early identification and management of frail CKD patients independent of the clinical setting of admission; however, more important than the method used is the need to identify and follow-up on frail CKD patients.

Interferon-induced degradation of the persistent hepatitis B virus cccDNA form depends on ISG20.

Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Interferons can diminish HBV cccDNA via APOBEC3-mediated deamination. Here, we show that overexpression of APOBEC3A alone is not sufficient to reduce HBV cccDNA that requires additional treatment of cells with interferon indicating involvement of an interferon-stimulated gene (ISG) in cccDNA degradation. Transcriptome analyses identify ISG20 as the only type I and II interferon-induced, nuclear protein with annotated nuclease activity. ISG20 localizes to nucleoli of interferon-stimulated hepatocytes and is enriched on deoxyuridine-containing single-stranded DNA that mimics transcriptionally active, APOBEC3A-deaminated HBV DNA. ISG20 expression is detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion mitigates the interferon-induced loss of cccDNA, and co-expression with APOBEC3A is sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires the concerted action of a deaminase and a nuclease. Our findings highlight that ISGs may cooperate in their antiviral activity that may be explored for therapeutic targeting.

Unusual high blood glucose in ketoacidosis as first presentation of type 1 diabetes mellitus

Diabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1 diabetes where it is typically associated with only moderately increased blood glucose. Here, we report the case of a 52-year-old female patient who was admitted to the emergency unit with severely altered mental status but stable vital signs. Laboratory results on admission revealed very high blood glucose (1687 mg/dL/93.6 mmol/L) and severe acidosis (pH <7) with proof of ketone bodies in serum and urine. Past history revealed a paranoid schizophrenia diagnosed 10 years ago and for which the patient was treated with risperidone for many years. Acute treatment with intravenous fluids, intravenous insulin infusion and sodium bicarbonate improved the symptoms. Further laboratory investigations confirmed diagnosis of autoimmune type 1 diabetes. After normalization of blood glucose levels, the patient could soon be discharged with a subcutaneous insulin therapy. Learning points: •• Diabetic ketoacidosis as first manifestation of type 1 diabetes can occur with markedly elevated blood glucose concentrations in elder patients. •• Atypical antipsychotics are associated with hyperglycemia and an increased risk of new-onset diabetes. •• First report of risperidone-associated diabetic ketoacidosis in new-onset type 1 diabetes. •• Patients treated with atypical antipsychotics require special care and regular laboratory examinations to detect hyperglycemia and diabetic ketoacidosis. •• In cases when the diagnosis is in doubt, blood gas analysis as well as determination of C-peptide and islet autoantibodies can help to establish the definite diabetes type.

Single Nucleotide Polymorphisms in the G-Protein Coupled Receptor Kinase 5 (GRK5) Gene are associated with Plasma LDL-Cholesterol Levels in Humans.

Genetically modified mice models suggest an important role for G-protein-coupled receptor kinase 5 (GRK5) in the pathophysiology of obesity and related disorders. We investigated whether single nucleotide polymorphisms (SNPs) in the gene encoding GRK5 affect cardiometabolic traits in humans. We genotyped 3 common SNPs in intron 1 (rs1980030, rs10466210, rs9325562) and one SNP in intron 3 (rs10886471) of GRK5 in 2332 subjects at risk for type 2 diabetes. Total- and visceral fat mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy. Insulin secretion and sensitivity were estimated during an OGTT and measured during the euglycemic, hyperinsulinemic clamp (n = 498). Carriers of the minor allele of rs10466210 and rs1980030 had higher total- and LDL-cholesterol levels (p = 0.0018 and p = 0.0031, respectively, for rs10466210; p = 0.0035 and p = 0.0081, respectively, for rs1980030), independently of gender, age, BMI and lipid-lowering drugs. The effects of rs10466210 withstood Bonferroni correction. Similar associations were observed with apolipoprotein B levels (p = 0.0034 and p = 0.0122, respectively). Carriers of the minor allele of rs10466210 additionally displayed a trend for higher intima-media thickness of the carotid artery (p = 0.075). GRK5 may represent a novel target for strategies aiming at lowering LDL-cholesterol levels and at modifying cardiovascular risk.

[Thromboembolic complication after ovarian stimulation]. / Thromboembolische Komplikation nach ovarieller Stimulation--Fall 1/2016.

HISTORY AND ADMISSION FINDINGS: We report on two pregnant women with dyspnoe and thoracic pain in the context of an ovarian hyperstimulation syndrome. INVESTIGATIONS: Both patients had pleural effusions. The first patient was diagnosed with pulmonary embolism via computer tomography. In the second patient, thrombosis of the upper part of the body including intracranial thrombosis was revealed via magnetic resonance and ultrasound imaging. In both cases, thrombosis was caused by ovarian hyperstimulation. DIAGNOSIS, TREATMENT AND COURSE: Therapy included anticoagulation with low molecular weight heparin and a drainage of the pleural effusions. One patient had an abortion in the 8th week of pregnancy, the second patient gave birth to two healthy children. CONCLUSIONS: Ovarian hyperstimulation syndrome is a potentially life-threatening disease, which should be considered as a differential diagnosis of causes of thromboembolic events in early pregnancy.

Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers.

OBJECTIVE: Phosphoinositide 3-kinase γ (PI3Kγ) is a G-protein-coupled receptor-activated lipid kinase mainly expressed in leukocytes and cells of the cardiovascular system. PI3Kγ plays an important signaling role in inflammatory processes. Since subclinical inflammation is a hallmark of atherosclerosis, obesity-related insulin resistance, and pancreatic ß-cell failure, we asked whether common genetic variation in the PI3Kγ gene (PIK3CG) contributes to body fat content/distribution, serum adipokine/cytokine concentrations, alterations in plasma lipid profiles, insulin sensitivity, insulin release, and glucose homeostasis. STUDY DESIGN: Using a tagging single nucleotide polymorphism (SNP) approach, we analyzed genotype-phenotype associations in 2,068 German subjects genotyped for 10 PIK3CG SNPs and characterized by oral glucose tolerance tests. In subgroups, data from hyperinsulinaemic-euglycaemic clamps, magnetic resonance spectroscopy of the liver, whole-body magnetic resonance imaging, and intravenous glucose tolerance tests were available, and peripheral blood mononuclear cells (PBMCs) were used for gene expression analysis. RESULTS: After appropriate adjustment, none of the PIK3CG tagging SNPs was significantly associated with body fat content/distribution, adipokine/cytokine concentrations, insulin sensitivity, insulin secretion, or blood glucose concentrations (p>0.0127, all; Bonferroni-corrected α-level: 0.0051). However, six non-linked SNPs displayed at least nominal associations with plasma HDL-cholesterol concentrations, two of them (rs4288294 and rs116697954) reaching the level of study-wide significance (p = 0.0003 and p = 0.0004, respectively). More precisely, rs4288294 and rs116697954 influenced HDL2-, but not HDL3-, cholesterol. With respect to the SNPs' in vivo functionality, rs4288294 was significantly associated with PIK3CG mRNA expression in PBMCs. CONCLUSIONS: We could demonstrate that common genetic variation in the PIK3CG locus, possibly via altered PIK3CG gene expression, determines plasma HDL-cholesterol concentrations. Since HDL2-, but not HDL3-, cholesterol is influenced by PIK3CG variants, PI3Kγ may play a role in HDL clearance rather than in HDL biogenesis. Even though the molecular pathways connecting PI3Kγ and HDL metabolism remain to be further elucidated, this finding could add a novel aspect to the pathophysiological role of PI3Kγ in atherogenesis.

Presence of fatty liver and the relationship between alcohol consumption and markers of inflammation.

Background and Aims. Local and systemic inflammation represent a major feature of atherosclerotic cardiovascular disease (CVD) and are also linked to nonalcoholic fatty liver disease (NAFLD). Studies indicate that NAFLD might be a risk factor for CVD whereas low-to-moderate alcohol consumption is associated with lower cardiovascular morbidity and mortality compared to abstainers and heavy drinkers. We hypothesize that FLD interacts with the effect of alcohol intake on markers of inflammation, and thus potentially on cardiovascular risk. Methods and Results. We evaluated alcohol consumption, markers of inflammation and sonographic criteria of FLD in 515 subjects, representing a subsample of a cross-sectional population based study (Echinococcus multilocularis and Internal Diseases in Leutkirch (EMIL) Study). Presence of FLD was markedly reduced in subjects drinking 0-20 g alcohol/d (19%), compared to nondrinkers (35%) and heavy drinkers (34-44.9%). Serum concentrations of inflammatory markers were substantially higher in subjects with FLD. However, presence of FLD showed no effect on the association between alcohol consumption and inflammatory biomarkers. Conclusions. Based on data from a population-based sample, there is no evidence for a link between FLD, alcohol consumption, and inflammatory cardiovascular risk markers. However, larger prospective studies are needed to confirm this.

[Rare cause of an abdominal emergency--case 6/2014]. / Seltene Ursache eines akuten Abdomens--Fall 6/2014.

HISTORY AND ADMISSION FINDINGS: We report on a 58-year-old male patient with abdominal and right-sided flank pain, who presented with the picture of an acute abdominal emergency. INVESTIGATIONS: Laboratory tests revealed evidence of an inflammation and a hematuria. In the Doppler duplex ultrasound and computed tomography, chronic idiopathic periaortitis was diagnosed. The inflammatory-fibrosing disease resulted in urine retention and rupture of the fornix of the right kidney. DIAGNOSIS, TREATMENT AND COURSE: After surgical implementation of an ureteral stent and initiation of immunosuppressive therapy, it came to an improvement of the symptoms. CONCLUSIONS: In the differential diagnosis of an acute abdominal emergency, diseases of the aorta should be taken into account. Especially in male patients with anatomical complications it is important to exclude an inflammatory-fibrosing disease.

NMR investigation of acrolein stability in hydroalcoholic solution as a foundation for the valid HS-SPME/GC-MS quantification of the unsaturated aldehyde in beverages.

Acrolein (propenal) is found in many foods and beverages and may pose a health hazard due to its cytotoxicity. Considerable knowledge gaps regarding human exposure to acrolein exist, and there is a lack of reliable analytical methods. Hydroalcoholic dilutions prepared for calibration purposes from pure acrolein show considerable degradation of the compound and nuclear magnetic resonance (NMR) spectroscopy showed that 1,3,3-propanetriol and 3-hydroxypropionaldehyde are formed. The degradation can be prevented by addition of hydroquinone as stabilizer to the calibration solutions, which then show linear concentration-response behaviour required for quantitative analysis. The stabilized calibration solutions were used for quantitative headspace solid-phase microextraction/gas chromatography-mass spectrometry (HS-SPME/GC-MS) determination of acrolein in alcoholic beverages with a detection limit of 14 µg L(-1). Of 117 tested alcoholic beverages, 64 were tested positive with the highest incidence in grape marc spirits and whiskey (100%, mean 252 µg L(-1)), followed by fruit spirits (86%, mean 591 µg/L(-1)), tequila (86%, mean 404 µg L(-1)), Asian spirits (43%, mean 54 µg L(-1)) and wine (9%, mean 0.7 µg L(-1)). Acrolein could not be detected in beer, vodka, absinthe and bottled water. Six of the fruit and grape marc spirits had acrolein levels above the World Health Organization (WHO) provisional tolerable concentration of 1.5 mg L(-1).

C-reactive protein specifically binds to Fcgamma receptor type I on a macrophage-like cell line.

C-reactive protein (CRP) is a prototype acute-phase protein that may be intimately involved in human disease. Its cellular receptors are still under debate; the main candidates are FcR for immunoglobulin G, as CRP was shown to bind specifically to FcgammaRI and FcgammaRIIa. Using ultrasensitive confocal live-cell imaging, we have studied CRP binding to FcgammaR naturally expressed in the plasma membranes of cells from a human leukemia cell line (Mono Mac 6). These macrophage-like cells express high levels of FcgammaRI and FcgammaRII. They were shown to bind fluorescently labeled CRP with micromolar affinity, KD = (6.6 +/- 1.5) microM. CRP binding could be inhibited by pre-incubation with human but not mouse IgG and was thus FcgammaR-specific. Blocking of FcgammaRI by an FcgammaRI-specific antibody abolished CRP binding essentially completely, whereas application of antibodies against FcgammaRII did not have a noticeable effect. In fluorescence images of Mono Mac 6 cells, the intensity patterns of bound CRP were correlated with those of FcgammaRI, but not FcgammaRII. These results provide clear evidence of specific interactions between CRP and FcgammaR (predominantly FcgammaRI) naturally expressed on macrophage-like cells.