Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value.

Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.

Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.

Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4-degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1.

Classification of neurovascular compression in typical hemifacial spasm: three-dimensional visualization of the facial and the vestibulocochlear nerves.

OBJECT: In this paper, the authors introduce a method of noninvasive anatomical analysis of the facial nerve-vestibulocochlear nerve complex and the depiction of the variable vascular relationships by using 3D volume visualization. With this technique, a detailed spatial representation of the facial and vestibulocochlear nerves was obtained. Patients with hemifacial spasm (HFS) resulting from neurovascular compression (NVC) were examined. METHODS: A total of 25 patients (13 males and 12 females) with HFS underwent 3D visualization using magnetic resonance (MR) imaging with 3D constructive interference in a steady state (CISS). Each data set was segmented and visualized with respect to the individual neurovascular relationships by direct volume rendering. Segmentation and visualization of the facial and vestibulocochlear nerves were performed with reference to their root exit zone (REZ), as well as proximal and distal segments including corresponding blood vessels. The 3D visualizations were interactively compared with the intraoperative situation during microvascular decompression (MVD) to verify the results with the observed microneurosurgical anatomy. RESULTS: Of the 25 patients, 20 underwent MVD (80%). Microvascular details were recorded on the affected and unaffected sides. On the affected sides, the anterior inferior cerebellar artery (AICA) was the most common causative vessel. The posterior inferior cerebellar artery, vertebral artery, internal auditory artery, and veins at the REZ of the facial nerve (the seventh cranial nerve) were also found to cause vascular contacts to the REZ of the facial nerve. In addition to this, the authors identified three distinct types of NVC within the REZ of the facial nerve at the affected sides. The authors analyzed the varying courses of the vessels on the unaffected sides. There were no bilateral clinical symptoms of HFS and no bilateral vascular compression of the REZ of the facial nerve. The authors discovered that the AICA is the most common vessel that interferes with the proximal and distal portions of the facial nerve without any contact between vessels and the REZ of the facial nerve on the unaffected sides. CONCLUSIONS: Three-dimensional visualization by direct volume rendering of 3D CISS MR imaging data offers the opportunity of noninvasive exploration and anatomical categorization of the facial nerve-vestibulocochlear nerve complex. Furthermore, it proves to be advantageous in establishing the diagnosis and guiding neurosurgical procedures by representing original MR imaging patient data in a 3D fashion. This modality provides an excellent overview of the entire neurovascular relationship of the cerebellopontine angle in each case.

Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyneuropathies?

OBJECTIVES: Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor NF-kappaB and subsequent expression of NF-kappaB regulated cytokines and is a possible pathomechanism in diabetic and in vasculitic polyneuropathies (PNP). We wanted to investigate whether the newly discovered RAGE pathway also contributes to the pathogenesis of various other PNP. METHODS: The presence of the RAGE ligand Nepsilon-Carboxymethyllysine (CML), the receptor itself and NF-kappaBp65 was studied in sural nerve biopsies of patients with alcohol-associated PNP (n=5), PNP owing to vitamin B12 deficiency (n=5), chronic inflammatory demyelinating PNP (CIDP, n=10), Charcot-Marie-Tooth disease (CMT) I or II (n= 10), PNP caused by monoclonal gammopathy of unknown significance (MGUS) (n=5), idiopathic PNP (n=10) and five normal controls by immunohistochemistry. Biopsies of either ten patients with diabetic and vasculitic PNP served as positive controls. RESULTS: CML, RAGE and NF-kappaBp65 were found in co-localization in epineurial vessels in PNP owing to vitamin B12 deficiency, diabetes and vasculitis and in the perineurium in diabetic PNP, vasculitic PNP and in some cases in CIDP and vitamin B12 deficiency. Only diabetic subjects demonstrated co-expression of the three antigens in endoneurial vessels. Increased CML, RAGE and NF-kappaBp65 expression was detected in endoneurial and epineurial mononuclear cells in CIDP and in vasculitic PNP. Additionally, RAGE expression in Schwann cells was significantly increased in diabetic PNP. DISCUSSION: These data suggest that activation of the RAGE pathway might contribute to the pathogenesis of CIDP, PNP owing to vitamin B12 deficiency, diabetes and vasculitis, whereas it does not seem to be involved in the pathogenesis of PNP owing to alcohol, MGUS, CMT I or II and idiopathic PNP.

Antrochoanal polyp and obstructive sleep apnoea in children.

Antrochoanal polyps were first documented in the 18th century. They represent one of the most common types of nasal polyps in children without cystic fibrosis. Only a few reports on children who had a history of snoring due to an antrochoanal polyp and only two cases where the antrochoanal polyp caused documented obstructive sleep apnoea (OSA) have been published so far. This report adds a third case of paediatric OSA induced by an antrochoanal polyp in a 12-year-old boy. After endonasal endoscopically-controlled polypectomy and a recurrence, transoral osteoplastic antrotomy in combination with endoscopic endonasal polypectomy eliminated the antrochoanal polyp and OSA was resolved. The authors have reviewed essential historical aspects about children suffering from snoring and/or OSA caused by an antrochoanal polyp.

Burden of care in amyotrophic lateral sclerosis.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal disease with unique demands on patients and carers. PATIENTS AND METHODS: The total burden of care and burden components in 37 ALS carers were measured using validated questionnaires. Furthermore, influencing factors (functional impairment of the patient, additional carers, participation in support groups) were assessed. RESULTS: The mean total burden of care for ALS was low compared with dementia, mixed neuropsychiatric and internal diseases, but was correlated with functional impairment (P = 0.003). The main burden components were 'personal and social restrictions' and 'physical and emotional problems'. Problem behaviour of the patients was low in general, but was higher in carers participating in support groups (P = 0.002). Carers supported by additional carers had higher strain. CONCLUSION: The low burden of ALS carers may be caused by the low incidence of problem behaviour in ALS patients. However, if problem behaviour exists, carers participate more often in support groups, indicating the need for assistance. The burden of care increases with the functional impairment. Support for the carers has to start sooner.