Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

Background and objectives

The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.

Design, setting, participants, & measurements

In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.

Results

Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, −2.1 to −0.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins.

Conclusions

In avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.     

Effect of Al-chlorophenoxyisobutyrate (Alufibrate) on pyruvate metabolism and on the fate of very low density lipoprotein lipids in hyperlipidemic patients

he exhalation of total CO₂ and ¹⁴ CQ₂ after an intravenous injection of either [1-¹⁴C]- or [2-¹⁴C]pyruvate was measured in six male patients with type IV hyperlipidemia who had previously been receiving treatment with alufibrate or placebo. Considerably more ¹⁴ CO₂ was exhaled after the injection of [1-¹⁴C]pyruvate than after the injection of [2-¹⁴C] pyruvate. Treatment with alufibrate only slightly diminished the oxidation of [1-¹⁴C]-pyruvate, but increased the oxidation of [2-¹⁴C] pyruvate to ¹⁴CO₂ by 25%. The total concentrations of [2-¹⁴C] pyruvate and its incorporation into the lipids of lipoprotein fractions were measured over 24 h. Alufibrate treatment decreased the serum concentration of VLDL by 53%, by reducing the turnover rate by 25% and increasing the net removal rate by about 30%. No effects on LDL and HDL lipid fractions were detected.     

Olfactory bulb involvement in neurodegenerative diseases

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson’s disease and other synucleinopathies, Alzheimer’s disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (n = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (P < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.     

Bleeding and non-bleeding phenotypes in patients with GGCX gene mutations

Functional limitations for the vitamin K cycle, caused either by mutations in gamma-glutamyl carboxylase or vitamin K epoxide reductase genes, result in hereditary deficiency of vitamin K-dependent coagulation factors (VKCFD1 and VKCFD2, respectively). Patients suffering from VKCFD often share several other anatomical irregularities which are not related to haemostasis. Here we report on nine patients, eight of them previously unreported, who presented with VKCFD1. All were examined with special attention to vitamin K-dependent coagulation factors as well as to bone and heart development and to other anatomical signs of embryonal vitamin K deficiency. In total, we detected ten mutations in the gamma-glutamyl carboxylase gene of which seven have not been previously reported. Most interestingly, additional non-bleeding phenotypes were observed in all patients including midfacial hypoplasia, premature osteoporosis, cochlear hearing loss, heart valve defects, pulmonary stenosis, or pseudoxanthoma elasticum-like phenotype. Undercarboxylated matrix Gla protein, osteocalcin, and periostin appear to be responsible for these defects which are also observed in cases of fetal warfarin syndrome.     

Selective peripheral denervation: comparison with pallidal stimulation and literature review

Patients with cervical dystonia who are non-responders to Botulinum toxin qualify for surgery. Selective peripheral denervation (Bertrand’s procedure, SPD) and deep brain stimulation of the globus pallidus (GPi-DBS) are available surgical options. Although peripheral denervation has potential advantages over DBS, the latter is nowadays more commonly performed. We describe the long-term outcome of selective peripheral denervation as compared with GPi-DBS, along with the findings of literature review. Twenty patients with selective peripheral denervation and 15 with GPi-DBS were included. Tsui scale, a visual analogue scale, and the global outcome score of the Toronto Western Spasmodic Torticollis Rating Scale were used to define a “combined global surgical outcome”. The “combined global surgical outcome” for patients with selective peripheral denervation or pallidal stimulation was respectively “bad” for 65 and 13.3 %, “fair-to-good” for 30 and 26.7 %, and “marked” improvement for 5 and 60 % (p < 0.001). Improvement on visual analogue scale (p < 0.002), global outcome score (p < 0.002), and Tsui score (p < 0.000) was larger for the pallidal stimulation group. Seventy-five percent of patients with selective peripheral denervation and 60 % of patients with pallidal stimulation reported side effects. Seven patients with selective peripheral denervation successively underwent GPi-DBS, with a further significant improvement in the Tsui score (?48.6 ± 17.4 %). GPi-DBS is to be preferred to selective peripheral denervation for the treatment of cervical dystonia because it produces larger benefit, even if it can have more potentially severe complications. GPi-DBS is also a valid alternative in case of failure of SPD.     

23Na-magnetic resonance imaging of the human lumbar vertebral discs: in vivo measurements at 3.0 T in healthy volunteers and patients with low back pain

Background context¹H magnetic resonance imaging (MRI) of the spine can rule out common causes of low back pain (LBP), such as disc protrusions or nerve root compression; however, no significant causal relation exists between morphology and the extent of symptoms. Functional MRI techniques, such as ²³Na, may provide additional information, allowing indirect assessment of vertebral glycosaminoglycan concentrations, decreases in which are associated with early degenerative changes.PurposeTo evaluate ²³Na-MRI of asymptomatic healthy volunteers and symptomatic patients with LPB and correlate the results to the Pfirrmann classification of MRI disc morphology.Study designRetrospective cohort study at an academic medical center.Patient sampleTwo groups were studied: (1) 55 healthy volunteers (31 men, 24 women; mean age 28.8 years) and (2) 12 patients (6 men, 6 women; mean age: 35.3 years) with a recent history of LBP.MethodsLumbar spines of the aforementioned groups were examined on a 3.0 T MRI scanner with morphological ¹H and ²³Na imaging. Intervertebral disc (IVD) ²³Na at each level was normalized (²³Na_norm). Distribution and differences between mean ²³Na_norm corresponding to each Pfirrmann classification were evaluated in the two study groups (analysis of variance). Linear correlations between ²³Na_norm, body mass index (BMI), and age were assessed (Pearson correlation coefficient). Gender-dependent differences were evaluated (paired t test).Outcome measuresPhysiological measure: IVD ²³Na_norm as determined by ²³Na-MRI.ResultsA normal distribution of ²³Na_norm was confirmed for both groups (p=.072 and p=.073, respectively). The mean Pfirrmann score statistically significantly differed between them (p<.0001). ²³Na_norm was statistically significantly reduced in degenerated IVDs (Pfirrmann scores 4+5) (p<.0001). No statistically significant differences were seen for the mean ²³Na_norm of IVDs with the same Pfirrmann score in healthy volunteers and patients (.469<p<.967). Age (0.007<R²<0.202) and BMI (0.074<R²<0.288) showed either weak or no correlation to ²³Na_norm. Mean ²³Na_norm was significantly (p=.0002) greater in women relative to men.ConclusionsThe results underline the feasibility and robustness of ²³Na-MRI of human IVDs and affirm, in a large cohort, decreases in ²³Na IVD content seen with disc degeneration.     

Dehydroepiandrosterone modulates T-cell response after major abdominal surgery

Background

The immune balance controlled by T-helper (Th)1 and Th2 cells is critical in protecting the host from pathogenic invasion, and its imbalance may increase susceptibility to infection in patients undergoing major surgery. The differentiation of naive T cells to Th1 and Th2 cells is largely driven by cytokines. In addition, steroid hormones have been shown to affect Th1/Th2 balance, particularly in autoimmune diseases. The regulation of Th1/Th2 balance in patients undergoing surgery and its potential clinical relevance remain unclear.

Materials and methods

Blood samples were obtained from patients both before and 2 h after major abdominal surgery. Peripheral blood mononuclear cells were isolated and cultured in wells coated with either anti-CD3 (direct T-cell stimulation) or phytohemagglutinin (PHA) (indirect T-cell stimulation), with or without 10⁻⁵ M dehydroepiandrosterone (DHEA). The release of interleukin (IL)-2, interferon gamma, and IL-10 was measured by an enzyme-linked immunosorbent assay, and the expression of CD4, CD8, and CD69 was determined by flow cytometry.

Results

DHEA decreased the release of IL-2 and IL-10 in directly (anti-CD3) and indirectly (PHA)-stimulated T cells from postoperative samples, whereas the release of interferon gamma in PHA-stimulated T cells was not affected. The distribution of CD4/CD8 was not significantly different after surgery or DHEA. DHEA was associated with a decrease in the expression of the activation marker CD69 on CD4⁺ T cells, whereas the activation of CD8⁺ T cells remained unchanged.

Conclusions

These results demonstrate that DHEA plays a critical role in controlling Th1/Th2 balance in the immediate postoperative period. Attenuation of both the Th1 and Th2 responses has been suggested to have immunoprotective effects. The role of DHEA in the regulation of Th1/Th2 balance in patients undergoing major abdominal surgery may, therefore, also be of significant clinical relevance and warrants further investigation.     

Side effects of proton beam therapy of choroidal melanoma in dependence of the dose to the optic disc and the irradiated length of the optic nerve

Graefe's Archive for Clinical and Experimental Ophthalmology - To analyze the impact of the dose to the optic disc and the irradiated length of the optic nerve on radiation-induced optic...