Abstract Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical ...features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and brain MRI lesions fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.
The production of high-value chemicals from natural resources as an alternative for petroleum-based products is currently expanding in parallel with biorefinery. The use of lignocellulosic biomass as ...raw material is promising to achieve economic and environmental sustainability. Filamentous fungi, particularly Aspergillus species, are already used industrially to produce organic acid as well as many enzymes. The production of lignocellulose-degrading enzymes opens the possibility for direct fungal fermentation towards organic acids such as itaconic acid (IA) and fumaric acid (FA). These acids have wide-range applications and potentially addressable markets as platform chemicals. However, current technologies for the production of these compounds are mostly based on submerged fermentation. This work showed the capacity of two Aspergillus species (A. terreus and A. oryzae) to yield both acids by solid-state fermentation and simultaneous saccharification and fermentation. FA was optimally produced at by A. oryzae in simultaneous saccharification and fermentation (0.54 mg/g wheat bran). The yield of 0.11 mg IA/g biomass by A. oryzae is the highest reported in the literature for simultaneous solid-state fermentation without sugar supplements. KCI Citation Count: 0
Background and purpose
Acquired neuromyotonia can occur in patients with thymoma, alone or in association with myasthenia gravis (MG), but the clinical prognostic significance of such comorbidity is ...largely unknown. The clinico‐pathological features were investigated along with the occurrence of neuromyotonia as predictors of tumour recurrence in patients with thymoma‐associated myasthenia.
Methods
A total number of 268 patients with thymomatous MG were studied retrospectively. Patients with symptoms of spontaneous muscle overactivity were selected for autoantibody testing using immunohistology for neuronal cell‐surface proteins and cell‐based assays for contactin‐associated protein 2 (CASPR2), leucine‐rich glioma inactivated 1 (LGI1), glycine receptor and Netrin‐1 receptor antibodies. Neuromyotonia was diagnosed according to the presence of typical electromyography abnormalities and/or autoantibodies against LGI1/CASPR2.
Results
Overall, 33/268 (12%) MG patients had a thymoma recurrence. Five/268 (2%) had neuromyotonia, four with typical autoantibodies, including LGI1 (n = 1), CASPR2 (n = 1) or both (n = 2). Three patients had Netrin‐1 receptor antibodies, two with neuromyotonia and concomitant CASPR2+LGI1 antibodies and one with spontaneous muscle overactivity without electromyography evidence of neuromyotonia. Thymoma recurrence was more frequent in those with (4/5, 80%) than in those without (28/263, 10%, P < 0.001) neuromyotonia. Neuromyotonia preceded the recurrence in 4/5 patients. In univariate analysis, predictors of thymoma recurrence were age at thymectomy odds ratio (OR) 0.95, 95% confidence interval (CI) 0.93–0.97, Masaoka stage ≥IIb (OR 10.73, 95% CI 2.38–48.36) and neuromyotonia (OR 41.78, 95% CI 4.71–370.58).
Conclusions
De novo occurrence of neuromyotonia in MG patients with previous thymomas is a rare event and may herald tumour recurrence. Neuronal autoantibodies can be helpful to assess the diagnosis. These observations provide pragmatic risk stratification for tumour vigilance in patients with thymomatous MG.
In this work, we develop a kinetic model of tumour growth taking into account the effects of clinical uncertainties characterising the tumours’ progression. The action of therapeutic protocols trying ...to steer the tumours’ volume towards a target size is then investigated by means of suitable selective-type controls acting at the level of cellular dynamics. By means of classical tools of statistical mechanics for many-agent systems, we are able to prove that it is possible to dampen clinical uncertainties across the scales. To take into account the scarcity of clinical data and the possible source of error in the image segmentation of tumours’ evolution, we estimated empirical distributions of relevant parameters that are considered to calibrate the resulting model obtained from real cases of primary glioblastoma. Suitable numerical methods for uncertainty quantification of the resulting kinetic equations are discussed and, in the last part of the paper, we compare the effectiveness of the introduced control approaches in reducing the variability in tumours’ size due to the presence of uncertain quantities.
•New kinetic model for tumour growth with clinical uncertainties.•The action of therapeutic protocols steers the tumours’ volume towards a target size.•The introduced therapies reduce the variability due to uncertain quantities.•Calibration of the model based on MRI scans.•Examples based on UQ methods for kinetic equations.
Aims
The purpose of this study was to isolate, characterize and determine the structure and the antibacterial activities of a bacteriocin produced by Carnobacterium maltaromaticum CPN, a strain ...isolated from unpasteurized milk Camembert cheese.
Methods and Results
This bacteriocin, termed maltaricin CPN, was produced at higher amounts in MRS broth at temperatures between 15°C and 25°C. It was purified to homogeneity from culture supernatant by using a simple method consisting of cation‐exchange and reversed‐phase chromatographies. Mass spectrometry showed that maltaricin was a 4427·29 Da bacteriocin. Its amino acid sequence was determined by Edman degradation which showed that it had close similarity with bacteriocins of the class IIa. Maltaricin CPN consisted in fact of 44 unmodified amino acids including two cysteine residues at positions 9 and 14 linked by a disulphide bond. The antimicrobial activity of maltaricin CPN covered a range of bacteria, with strong activity against many species of Gram‐positive bacteria, especially the food‐borne pathogen Listeria monocytogenes, but no activity against Gram‐negative ones.
Conclusions
In the studied conditions, C. maltaromaticum CPN produced a new class IIa bacteriocin with strong anti‐Listeria activity.
Significance and Impact of the Study
The study covers the purification and the structural characterization of a new bacteriocin produced by strain C. maltaromaticum CPN isolated from Camembert cheese. Its activity against strains of L. monocytogenes and higher production rates at relatively low temperatures show potential technological applications to improve the safety of refrigerated food.
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Insulin delivery by oral route would be ideal, but has no effect, due to the harsh conditions of the gastrointestinal tract. Protection of insulin using encapsulation in ...self-assembled particles is a promising approach. However, the lack of stability of this kind of particles in biological environments induces a low bioavailability of encapsulated insulin after oral administration. The objective of this work was to evaluate the effect of two stabilisation strategies alone or combined, freeze-drying and cross-linking, on insulin-loaded chitosan NPs, and to determine their bioefficiency in vitro and in vivo. NPs were prepared by complex coacervation between insulin and chitosan, stabilised either by cross linking with sodium tripolyphosphate solution (TPP), by freeze-drying or both treatments. In vitro bioefficiency NP uptake was evaluated by flow cytometry on epithelial models (Caco-2/RevHT29MTX (mucus secreting cells)). In vivo, NPs were injected via catheter in the peritoneum or duodenum on insulinopenic rats. Freeze-drying increased in size and charge (+15% vs control 412±7nm; +36±0.3mV) in comparison with cross linking which decreased NP size (−25%) without impacting the NP charge. When combined the consecutive treatments reduced NPs size and increased charges as compared to standard level. Freeze drying is necessary to prevent the destruction of NP in intestinal environment in comparison with no freeze dryed one where 60% of NP were destroyed after 2h. Additionally freeze drying combined with cross linking treatments improved bioefficiency of NP with uptake in cell increased when mucus is present. Combination of both treatment showed a protection of insulin in vivo, with a reduction of glycemia when NPs were administrated. This work showed that the combination of freeze drying and cross linking treatment is necessary to stabilize (freeze-drying) and increase bioefficiency (cross-linking) of self assembled NP in the delivery of insulin in vitro and in vivo.
Background and purpose
Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus‐based ...diagnostic criteria (AE‐DC) allow clinic‐serological subgrouping of AE, with unclear prognostic implications. The impact of AE‐DC on patients’ management was studied, focusing on the subgroup of Ab‐negative‐AE.
Methods
This was a retrospective multicenter study on patients fulfilling AE‐DC. All patients underwent Ab testing with commercial cell‐based assays (CBAs) and, when available, in‐house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab‐positive‐AE N‐methyl‐d‐aspartate‐receptor encephalitis (NMDAR‐E), Ab‐positive limbic encephalitis (LE), definite‐AE or Ab‐negative‐AE (Ab‐negative‐LE, probable‐AE, possible‐AE).
Results
Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab‐negative cases, in‐house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE‐DC, 81 (68.6%) with Ab‐positive‐AE (Ab‐positive‐LE, 40; NMDAR‐E, 32; definite‐AE, nine) and 37 (31.4%) with Ab‐negative‐AE (Ab‐negative‐LE, 17; probable/possible‐AE, 20). Clinical phenotypes were similar in Ab‐positive‐LE versus Ab‐negative‐LE. Twenty‐four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab‐positive or Ab‐negative. Ab‐positive‐AE patients were treated earlier than Ab‐negative‐AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second‐line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first‐line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00–1.04).
Conclusions
In‐house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab‐positive‐AE underestimation. Notwithstanding this limitation, our findings suggest that Ab‐negative‐AE and Ab‐positive‐AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab‐negative‐AE patients risk worse responses due to delayed and less aggressive treatments.
Background and purpose
Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a ...second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment.
Methods
In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m
2
i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints.
Results
Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients.
Conclusion
Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time.
Trial registration
: This study is registered with ClinicalTrials.gov, number NCT01989884.
Background and purpose
Patients with a history of brain radiotherapy can experience acute stroke‐like syndromes related to the delayed effects of brain radiation, including stroke‐like migraine ...attacks after radiation therapy syndrome, peri‐ictal pseudoprogression and acute late‐onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long‐term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description.
Methods
Cases were collected, both prospectively and retrospectively, amongst six neuro‐oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke‐like syndromes was performed to corroborate our findings.
Results
Thirty‐two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke‐like syndromes. Patients with stroke‐like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy‐three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high‐dose steroids in 65% of cases. Twenty‐two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow‐up 3.5 years). A literature review identified 87 additional stroke‐like cases with similar characteristics.
Conclusions
Stroke‐like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.
Itaconic acid (IA) is a dicarboxylic acid included in the US Department of Energy's (DOE) 2004 list of the most promising chemical platforms derived from sugars. IA is produced industrially using ...liquid-state fermentation (LSF) by Aspergillus terreus with glucose as the carbon source. To utilize IA production in renewable resource-based biorefinery, the present study investigated the use of lignocellulosic biomass as a carbon source for LSF. We also investigated the production of fumaric acid (FA), which is also on the DOE's list. FA is a primary metabolite, whereas IA is a secondary metabolite and requires the enzyme cis-aconitate decarboxylase for its production. Two lignocellulosic biomasses (wheat bran and corn cobs) were tested for fungal fermentation. Liquid hydrolysates obtained after acid or enzymatic treatment were used in LSF. We show that each treatment resulted in different concentrations of sugars, metals, or inhibitors. Furthermore, different acid yields (IA and FA) were obtained depending on which of the four Aspergillus strains tested were employed. The maximum FA yield was obtained when A. terreus was used for LSF of corn cob hydrolysate (1.9% total glucose); whereas an IA yield of 0.14% was obtained by LSF of corn cob hydrolysates by A. oryzae.
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