Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer's Disease from Frontotemporal Lobar Degeneration.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aß42 ≤1000 pg/mL, pTau181/Aß42 ratio >0.024, and tTau/Aß42 ratio >0.28) and optimized cut-offs based on Youden's index. RESULTS: AUC-based performance was similarly good for the pTau181/Aß42 ratio (AUC=0.841; 95% CI: 0.759-0.923), pTau181/Aß40 ratio (AUC=0.837; 95% CI: 0.754-0.919), Aß42/Aß40 ratio (AUC=0.829; 95% CI: 0.746-0.912), tTau/Aß42 ratio (AUC=0.822; 95% CI: 0.736-0.908), pTau181/Aß42/Aß40 ratio (AUC=0.817; 95% CI: 0.734-0.901), and Aß42 (AUC=0.812; 95% CI: 0.722-0.902). Performance was slightly lower for the tTau/Aß42/Aß40 ratio (AUC=0.799; 95% CI: 0.713-0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707-0.880), tTau/Aß40 ratio (AUC=0.751; 95% CI: 0.657-0.844), and tTau alone (AUC=0.706; 95% CI: 0.613-0.799). The highest qualitative performance was observed with the pTau181/Aß42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

Maximizing the production of butyric acid from food waste as a precursor for ABE-fermentation.

The current study reports on the maximization of butyric acid production from food waste using a mixed microbial fermentation. In semi-continuous fermentations the effect of three different pH values (5.5, 7.0 and 9.0), three different temperatures (37°C, 55°C and 70°C) and two levels of hydraulic retention time (HRT, 2days and 6days) on the formation of butyric acid as well as total volatile fatty acid production (tVFA) were investigated. Overall, pH5.5 provided the lowest butyric acid concentrations regardless of the temperature and the HRT. At mesophilic temperature (37°C) alkaline conditions (pH9.0) lead to a strong incline of tVFA as well as butyric acid concentration probably due to a decreased solubilization of the substrate. However, most efficient in terms of butyric acid production was the fermentation conducted at 55°C and pH7 where a butyric acid concentrations of 10.55g/L (HRT 2days) and 13.00g/L (HRT 6days) were achieved. Additional experiments at 70°C showed declining butyric acid production. Increase of the HRT from 2days to 6days provided an increment of butyric acid concentration throughout almost all experimental settings. However, regarding volumetric productivity the increase in concentration does not compensate for the bigger reactor volume required to establish a higher HRT. At pH7 and 55°C the resulting volumetric production rates were 5.27g/L∗d at a HRT 2days and only 2.17g/L∗d at a HRT of 6days.

[Posterior cortical atrophy. Pathology, diagnosis and treatment of a rare form of dementia]. / Posteriore kortikale Atrophie. Pathologie, Diagnostik und Behandlung einer seltenen Form der Demenz.

The syndrome of posterior cortical atrophy (PCA) is a rare clinical manifestation of several neurodegenerative diseases which affect the parieto-occipital cortex. The most frequent underlying pathology is Alzheimer's disease but some cases are caused by Lewy body disease, progressive subcortical gliosis, corticobasal degeneration or prion diseases. The most prominent clinical feature of PCA is complex visual disturbances including object agnosia, simultanagnosia, optical ataxia and oculomotor apraxia while basic visual functions remain intact. These deficits lead to multiple impairments in activities of daily living that require visual control. On progression of the disease amnestic, apraxic and dysexecutive symptoms occur so that a global dementia gradually emerges. At the core of the diagnostic work-up are a detailed patient history, accurate analysis of behavior and neuropsychological testing. Structural and functional brain imaging are suitable to demonstrate the localization of the disease process. Measurement of cerebrospinal fluid proteins (e.g. beta amyloid, tau, phospho-tau and 14-3-3) serves to confirm or exclude Alzheimer's disease or prion diseases. The mainstay of treatment are non-pharmacological interventions to support activities of daily living and personal independence. These treatments include cognitive training and compensatory strategies which can be prescribed as neuropsychological treatment or occupational therapy. If Alzheimer's disease or Lewy body disease is the likely cause, a treatment with cholinesterase inhibitor may be tried. Caregiver education and support are another essential part of the treatment regimen as with all forms of dementia.

Counteracting ammonia inhibition in anaerobic digestion by removal with a hollow fiber membrane contactor.

The aim of the current study was to investigate the feasibility of membrane contactors for continuous ammonia (NH3-N) removal in an anaerobic digestion process and to counteract ammonia inhibition. Two laboratory anaerobic digesters were fed slaughterhouse wastes with ammonium (NH4⁺) concentrations ranging from 6 to 7.4 g/L. One reactor was used as reference reactor without any ammonia removal. In the second reactor, a hollow fiber membrane contactor module was used for continuous ammonia removal. The hollow fiber membranes were directly submerged into the digestate of the anaerobic reactor. Sulfuric acid was circulated in the lumen as an adsorbent solution. Using this set up, the NH4⁺-N concentration in the membrane reactor was significantly reduced. Moreover the extraction of ammonia lowered the pH by 0.2 units. In combination that led to a lowering of the free NH3-N concentration by about 70%. Ammonia inhibition in the reference reactor was observed when the concentration exceeded 6 g/L NH4⁺-N or 1-1.2 g/L NH3-N. In contrast, in the membrane reactor the volatile fatty acid concentration, an indicator for process stability, was much lower and a higher gas yield and better degradation was observed. The chosen approach offers an appealing technology to remove ammonia directly from media having high concentrations of solids and it can help to improve process efficiency in anaerobic digestion of ammonia rich substrates.

Low dose endoluminal photodynamic therapy improves murine T cell-mediated colitis.

BACKGROUND AND STUDY AIMS: Low dose photodynamic therapy (LDPDT) may modify the mucosal immune response and may thus provide a therapy for Crohn's disease. We evaluated the efficacy and safety of this technique in a murine T cell-mediated colitis model. METHODS: The safety of LDPDT was first tested in BALB/c mice. Naïve T cells were used to induce colitis in mice with severe combined immunodeficiency, which were followed up endoscopically, and a murine endoscopic index of colitis (MEIC) was developed. The efficacy of LDPDT (10 J/cm (2); delta-aminolevulinic acid, 15 mg/kg bodyweight) was then tested on mice with moderate colitis, while a disease control group received no treatment. The MEIC, weight, length, and histology of the colon, cytokine expression indices, number of mucosal CD4 (+) T cells, percentage of apoptotic CD4 (+) T cells, body weight, and systemic side effects were evaluated. RESULTS: LDPDT improved the MEIC ( P = 0.011) and the histological score ( P = 0.025), diminished the expression indices of the proinflammatory cytokines, interleukin-6 ( P = 0.042), interleukin-17 ( P = 0.029), and interferon-gamma ( P = 0.014), decreased the number of mucosal CD4 (+) T cells, and increased the percentage of apoptotic CD4 (+) T cells compared with the disease control group. No local or systemic side effects occurred. CONCLUSION: LDPDT improves murine T cell-mediated colitis, decreases the proinflammatory cytokines interleukin-6, interleukin-17, and interferon-gamma, and decreases the number of CD4 (+) T cells. No adverse events were observed. Therefore, this technique is now being evaluated in patients with inflammatory bowel disease.

The pharmacokinetics and safety of porfimer after repeated administration 30-45 days apart to patients undergoing photodynamic therapy.

BACKGROUND: Porfimer is an intravenous (i.v.) injectable photosensitizing agent used in the photodynamic treatment of tumours and of high-grade dysplasia in Barrett's oesophagus. AIM: To assess the pharmacokinetics as well as the safety profiles of porfimer after a first and a second dose administered 30-45 days apart in patients undergoing photodynamic therapy. METHODS: Nineteen patients (16 with cholangiocarcinoma) were enrolled. Porfimer sodium was administered by i.v. injection over 3-5 min. Blood samples were collected prior to starting i.v. drug injection and postdose at different time points after the first and second administrations. RESULTS: Porfimer exposure values after the second administration were statistically higher than those observed after the first administration, suggesting a slight accumulation of porfimer following repeated administration. The apparent mean elimination half-life of porfimer increased from 410 h after the first administration to 725 h after the second administration. The safety profiles of porfimer after a first and a second administration were similar and did not raise additional concern. Eight patients experienced nine serious adverse events. Only photosensitivity was deemed study-drug related. CONCLUSION: Porfimer appears to display a safe and tolerable profile when used in patients requiring a second photodynamic therapy within 45 days.

Incorporation of 2,4,6-trinitrotoluene (TNT) transforming bacteria into explosive formulations.

Pseudomonas putida GG04 and Bacillus SF have been successfully incorporated into an explosive formulation to enhance biotransformation of TNT residues and/or explosives which fail to detonate due to technical faults. The incorporation of the microorganisms into the explosive did not affect the quality of the explosive (5 years storage) in terms of detonation velocity while complete biotransformation of TNT moieties upon transfer in liquid media was observed after 5 days. The incorporated microorganisms reduced TNT sequentially leading to the formation of hydroxylaminodinitrotoluenes (HADNT), 4-amino-2,6-dinitrotoluenes; 2-amino-4,6-dinitrotoluenes, different azoxy compounds; 2,6-diaminonitrotoluenes (2,4-DAMNT) and 2,4-diaminonitrotoluenes (2,6-DAMNT). However, the accumulation of AMDNT and DAMNT (major dead-end metabolites) was effectively prevented by incorporating guaiacol and catechol during the biotransformation process.

Cold atoms and molecules in self-assembled dipolar lattices.

We study the realization of lattice models, where cold atoms and molecules move as extra particles in a dipolar crystal of trapped polar molecules. The crystal is a self-assembled floating mesoscopic lattice structure with quantum dynamics given by phonons. We show that within an experimentally accessible parameter regime extended Hubbard models with tunable long-range phonon-mediated interactions describe the effective dynamics of dressed particles.

Subpixel tracking for the analysis of outer hair cell movements.

CONCLUSION: Videomicroscopy with subpixel analysis is an excellent system for quantification of outer hair cell (OHC) movements. The resolution of a few nanometers is accurate enough to show induced differences of electromotility. OBJECTIVE: Electromotility of OHCs is a voltage-dependent process resulting from a membrane protein named prestin. Voltage sensitivity is conferred to prestin by intracellular anions. Reduction of these anions reduces electromotility. Videomicroscopy and subpixel tracking combine video-based analysis with a resolution of few nanometers. The aim of this study was to show the feasibility of a system for quantification of OHC movements. MATERIALS AND METHODS: Electromotility was investigated under normal and reduced intracellular chloride conditions. Cells were stimulated by the patch-clamp technique. Voltage steps were 500 ms long, ranging from -170 to +30 mV in 10 mV steps. RESULTS: As in previous studies our results show the following. The direction of OHC movement depends on the polarity of voltage steps, length changes are not equal for symmetrical voltage steps of opposite polarity, average shortening for a depolarizing step (-70 mV to +30 mV) is about 13 nm/mV. Hyperpolarization (-70 mV to -170 mV) on average evokes elongations of about 3 nm/mV. Half maximal chloride concentration reduces motility by 14%; half maximal electromotility is reached by a 94% reduction of chloride.

[Klatskin tumors--diagnostic and interventional therapy]. / Klatskin-Tumoren--Diagnostik und interventionelle Therapie.

Klatskin tumors are defined as malignant tumors of the bile duct involving the bifurcation and intrahepatic bile ducts. The most common presenting clinical feature, obstructive jaundice, usually occurs with advanced disease. Diagnostic tools currently available are therefore either performed too late or are not able to detect early disease stage. Imaging procedures for diagnosis and staging are ultrasonography, magnetic resonance imaging with cholangiopancreaticography, intravenous bolus-enhanced spiral computed tomography and endoscopic retrograde cholangiopancreaticography. Before initiating any palliative measure, a proper staging and a surgical consultation at a hepatobiliary center is necessary. To assess resectability, additional diagnostic methods like angiography, positron emission tomography, cholangioscopy, endoscopic or intraluminal ultrasonography and finally even explorative laparoscopy may be required. At time of diagnosis only a small percentage of Klatskin tumors is curative resectable. Therefore, palliative treatment options play an important role. Endoprostheses insertion is the method of choice to relieve jaundice. Although it improves quality of life, it does not seem to improve survival time. Definitive evidence for a benefit of additional radio and/or chemotherapy is still missing. Photodynamic therapy, a light therapy, is the first approach leading to an improvement of cholestasis and quality of life as well as to a prolongation of survival time. PDT should therefore be offered to all patients with nonresectable cholangiocarcinoma.

[Contribution of endoscopy in palliative oncology (endoprosthesis, photodynamic therapy, parenteral nutrition]. / Apport de l'endoscopie en oncologie palliative (endoprothèse, thérapie photodynamique, sonde de nutrition).

The aim of this review is to give an overview of palliative endoscopic treatment options in patients with advanced cancers of the esophagus, stomach, pancreas and bile ducts. With regard to esophageal cancers, we will also speak about curative endoscopic treatment (photodynamic therapy, mucosectomy) of early cancers and dysplasias. We will not approach to this subject in other types of carcinoma, since this has already been covered by the acquisitions of the last years.

[Endoscopic diagnosis and therapy for gastrointestinal bleeding]. / Endoskopische Diagnostik und Therapie der gastrointestinalen Blutung.

Gastrointestinal bleeding is still one of the most frequent medical emergencies. Despite improvements in endoscopic diagnosis and therapy, mortality from bleeding is still high (15%). Since conclusive trials are lacking, the endoscopist often has to rely on personal experience in the selection of therapeutic options. Therefore this article gives an overview of new publications in this field and recommendations based on personal experience.

[Treatment of vitally endangered anorexia nervosa patients based on guardianship laws]. / Behandlung vital gefährdeter Anorexia-nervosa-Patienten unter Berücksichtigung der Möglichkeiten des Betreuungsrechts.

Anorexia nervosa is a psychiatric disorder occurring primarily in young women. Especially when chronic or the body mass index is less than 12 kg/m(2), it has a mortality of up to 20%. Often these patients are admitted to emergency units and treated internistically. If they accept psychiatric treatment, they are normally transferred to specialized psychosomatic units for further therapy. If patients are not able to accept necessary further therapy to overcome the danger to health and life, the question arises in terms of guardianship law of whether they are able to handle their personal concerns alone. After several vitally endangered anorexia nervosa patients had been admitted to our closed psychiatric ward, we developed a therapeutic concept for this subgroup of patients, taking the possibilities of guardianship law into account. This concept aims at restoring the body weight continuously and finally enable the patients to be transferred to less restrictive psychosomatic units. The chosen treatment is shown with the therapy courses of 25 patients treated according to this concept.

Is early endoscopy in the emergency room beneficial in patients with bleeding peptic ulcer? A "fortuitously controlled" study.

BACKGROUND AND STUDY AIMS: In previous randomized trials, early endoscopy improved the outcome in patients with bleeding peptic ulcer, though most of these studies defined "early" as endoscopy performed within 24 hours after admission. Using the length of hospital stay as the primary criterion for the clinical outcome, we compared the results of endoscopy done immediately after admission (early endoscopy in the emergency room, EEE) with endoscopy postponed to a time within the first 24 hours after hospitalization, but still during normal working hours ("delayed" endoscopy in the endoscopy unit, DEU). PATIENTS AND METHODS: We conducted a retrospective analysis of data from 81 consecutive patients with bleeding peptic ulcer admitted in 1997 and 1998 (age range 16 - 90 years). Of these 81 patients, 38 underwent DEU (the standard therapy at the hospital) and 43 underwent EEE. Patients in the two groups were comparable with regard to admission criteria, were equally distributed with respect to their risk of adverse outcome (assessed using the Baylor bleeding score and the Rockall score), and differed only in the treatment they received. Endoscopic hemostasis was performed whenever possible in all patients with Forrest types I, IIa, and IIb ulcer bleeding. RESULTS: We found similar rates in the two groups for recurrent bleeding (16 % in DEU patients vs. 14 % in EEE patients), persistent bleeding (8 % in DEU patients vs. none in EEE patients), medical complications (21 % in DEU patients vs. 26 % in EEE patients), the need for surgery (8 % in DEU patients vs. 9 % in EEE patients), and the length of hospital stay (5.1 days for DEU patients vs. 5.9 days for EEE patients). None of the differences between the two groups in these parameters were statistically significant. None of the patients died. CONCLUSIONS: Early endoscopy in an emergency room did not improve the clinical outcome in our 81 consecutive patients with bleeding peptic ulcer.

Small bowel involvement in Crohn's disease: a prospective comparison of wireless capsule endoscopy and computed tomography enteroclysis.

BACKGROUND: Wireless capsule endoscopy (WCE) offers endoscopic access to the small bowel and may therefore change diagnostic and therapeutic strategies in small bowel diseases. AIM: The aim of this prospective study was to validate the gain in information and therapeutic impact of WCE in patients with Crohn's disease. METHODS: Fifty six consecutive patients with Crohn's disease underwent computed tomography (CT) enteroclysis, and if stenoses <10 mm were excluded, WCE was carried out. RESULTS: In 15 patients (27%), WCE could not be performed due to strictures detected by CT enteroclysis. From the other 41 patients, jejunal or ileal lesions were found in 25 patients by WCE compared with 12 by CT enteroclysis (p=0.004). This gain in information was mainly due to detection of small mucosal lesions such as villous denudation, aphthoid ulcerations, or erosions. Both methods were not significantly different in the detection of lesions in the terminal/neoterminal ileum (WCE 24 patients, CT enteroclysis 20 patients). Therapy was changed due to WCE findings in 10 patients. Consecutively, all of them improved clinically. CONCLUSIONS: Capsule endoscopy improves the diagnosis of small bowel Crohn's disease. This may have significant therapeutic impact.

Endoscopic injection of mitomycin adsorbed on carbon particles for advanced esophageal cancer: a pilot study.

BACKGROUND AND STUDY AIMS: Patients with advanced, unresectable esophageal carcinoma have an extremely poor prognosis, with dysphagia being the major problem. The aim of this prospective pilot study was to evaluate the efficacy of local injections of mitomycin adsorbed onto activated carbon particles (MMC-CH) in advanced unresectable esophageal squamous-cell carcinoma. The primary outcome parameter was survival time; secondary parameters were dysphagia and quality of life. PATIENTS AND METHODS: Ten consecutive patients with stage IV esophageal carcinoma (age: median 58, range 32 - 78), median tumor length 11 cm (range 5 - 15) received four weekly injections of 15 mg (10 ml) MMC-CH into the endoscopically visualized tumor, via a 5-mm sclerotherapy needle. The tumor stage, symptom score, and quality of life (measured using the Karnofsky index) were assessed before and after therapy and every 2 months thereafter. RESULTS: The median survival time after MMC-CH therapy was 16 weeks (95 % CI, 11.7 to 20.4). Dysphagia was reduced ( P < 0.001) in parallel with the reduction in the tumor mass ( r = 0.82, P = 0.01). The Karnofsky index ( P < 0.01) also improved after MMC-CH treatment. MMC-CH was well tolerated, and no side effects were observed. CONCLUSIONS: Endoluminal MMC-CH therapy appears to be an effective, inexpensive, and well-tolerated treatment for unresectable advanced squamous-cell esophageal carcinoma.

Diagnostic yield of wireless capsule enteroscopy in comparison with computed tomography enteroclysis.

BACKGROUND AND STUDY AIMS: It is still difficult to visualize changes in the small intestine. Wireless capsule enteroscopy is a new method that promises to provide new insights into the small intestine. In a prospective study, the diagnostic yield of wireless enteroscopy was therefore compared with computed tomography (CT) enteroclysis. PATIENTS AND METHODS: Twenty-two patients with suspected small-bowel pathology underwent CT enteroclysis and wireless capsule enteroscopy examinations, conducted by two independent blinded investigators. The results of the two investigations (diagnoses and the number, extent, and location of lesions detected) were compared by a third investigator. RESULTS: The patients included in the study had obscure gastrointestinal bleeding (n = 8), Crohn's disease (n = 8), unexplained diarrhea (n = 5), or suspected carcinoid tumor (n = 1). Pathological lesions were detected using capsule enteroscopy in 13 patients (59 %) and using CT enteroclysis in eight (36 %; P = 0.12). In seven patients (one case each of colonic Crohn's disease, diverticulitis, Meckel's diverticulum, carcinoid tumor, mesothelioma, colonic polyps, and irritable bowel syndrome), no pathological changes were found in the small intestine using either method. The diagnosis was established by wireless capsule enteroscopy in four patients with obscure bleeding, whereas CT enteroclysis was positive in only one patient ( P = 0.1). Crohn's disease was found in two patients with unexplained diarrhea. Small-bowel lesions were identified in six patients with known Crohn's disease using capsule enteroscopy or CT enteroclysis. The only side effect of wireless capsule enteroscopy observed was abdominal pain in one patient with Crohn's disease. There were no serious side effects with CT enteroclysis. CONCLUSIONS: Wireless capsule enteroscopy detects more small-bowel lesions than CT enteroclysis in patients with obscure gastrointestinal bleeding and Crohn's disease.

Methylation status of p14ARF and p16INK4a as detected in pancreatic secretions.

The clinical management of pancreatic disease is often hampered by a lack of tissue diagnosis. Endoscopic pancreatography offers the opportunity to investigate exfoliated cells. However, the significance of mere cytological investigation is compromised by an insufficient sensitivity. The evaluation of the molecular background of carcinogenesis hopefully is capable of providing more sensitive diagnostic markers. The p16INK4a-/retinoblastoma tumour-suppressive pathway has been shown to be involved in the development of near to all pancreatic neoplasms. p14ARF is another tumour suppressor located in the immediate neighbourhood of p16INK4a. Promoter methylation has been demonstrated to be a major inactivating mechanism of both genes. We sought to further evaluate the role of the gene locus INK4a methylation status in the endoscopic differentiation of chronic inflammatory and neoplastic pancreatic disease. Pancreatic fluid specimens of 61 patients with either pancreatic carcinoma (PCA: 39), chronic pancreatitis (CP: 16) or a normal pancreatogram (NAD: 6) were retrieved. In order to detect methylation of either the p14ARF or the p16INK4a promoter a methylation-specific PCR protocol was applied. While 19 out of 39 patients with PCA showed p16 promoter methylation (49%), none of the 16 patients with CP revealed p16 promoter methylation. p14ARF methylation was found in a lower percentage of PCA specimens and in none of the samples of patients with CP. These results suggest a specific significance of INK4a for the development of malignant pancreatic disease. Our data further indicate a potential role for INK4a methylation as a diagnostic marker in the endoscopic differentiation of benign and malignant pancreatic disease.