A variable neurodegenerative phenotype with polymerase gamma mutation

mtDNA replication and repair, causes mitochondrial diseases including autosomal dominant progressive external ophthalmoplegia (PEO),1 childhood hepato-encephalopathy (Alpers– Huttenlocher syndrome), adult-onset spinocerebellar ataxia, and sensory nerve degeneration with dysarthria and ophthalmoparesis (SANDO)

Linkage Evidence for a Two-Locus Inheritance of LQT-Associated Seizures in a Multigenerational LQT Family With a Novel KCNQ1 Loss-of-Function Mutation

Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures

Visual dysfunction, but not retinal thinning, following anti-NMDA receptor encephalitis

Objective: To assess structural and functional changes in the afferent visual system following anti-NMDA receptor (NMDAR) encephalitis. Methods: In this cross-sectional study including 31 patients after acute NMDAR encephalitis and matched healthy controls, visual function was assessed as high-contrast visual acuity using Early Treatment Diabetic Retinopathy Study charts and low-contrast sensitivity using Functional Acuity Contrast Test. Retinal changes were measured using optical coherence tomography with assessment of peripapillary retinal nerve fiber layer (pRNFL) and macular intraretinal layer thicknesses. Residual clinical impairment was described using the modified Rankin Scale. Results: High-contrast (logMAR 0.02 ± 0.14 vs −0.09 ± 0.14, p < 0.001) and low-contrast (area under the curve 1.89 ± 0.21 vs 2.00 ± 0.26, p = 0.039) visual acuity were reduced in patients in comparison to healthy controls. More severely affected patients performed worse in visual acuity testing than patients with good recovery (logMAR −0.02 ± 0.11 vs 0.08 ± 0.17, p = 0.030). In contrast, patients did not differ from matched healthy controls in pRNFL or in thickness of intraretinal layers, including the ganglion cell complex, the inner nuclear layer, the outer nuclear and plexiform layers, and the photoreceptor layer. Conclusions: After acute NMDAR encephalitis, patients have mild visual dysfunction in comparison to matched healthy controls, while retinal structure appears unaltered. These observations could point to an impairment of anterior or posterior visual pathway NMDAR function that is similar to dysfunction of NMDAR in cerebral cortex and subcortical structures. Alternatively, residual cognitive impairment might reduce visual function

Thermodynamical Consistent Modeling and Analysis of Nematic Liquid Crystal Flows

The general Ericksen-Leslie system for the flow of nematic liquid crystals is reconsidered in the non-isothermal case aiming for thermodynamically consistent models. The non-isothermal model is then investigated analytically. A fairly complete dynamic theory is developed by analyzing these systems as quasilinear parabolic evolution equations in an $L^p-L^q$-setting. First, the existence of a unique, local strong solution is proved. It is then shown that this solution extends to a global strong solution provided the initial data are close to an equilibrium or the solution is eventually bounded in the natural norm of the underlying state space. In these cases, the solution converges exponentially to an equilibrium in the natural state manifold

Altered paired associative stimulation-induced plasticity in NMDAR encephalitis

Objective: To determine whether neurophysiological mechanisms indicating cortical excitability, long-term potentiation (LTP)-like plasticity, GABAergic and glutamatergic function are altered in patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and whether they can be helpful as markers of diagnostic assessment, disease progression, and potentially therapy response. Methods: Neurophysiological characterizations of patients with NMDAR encephalitis (n = 34, mean age: 28 ± 11 years; 30 females) and age/gender-matched healthy controls (n = 27, 28.5 ± 10 years; 25 females) were performed using transcranial magnetic stimulation-derived protocols including resting motor threshold, recruitment curve, intracortical facilitation, short intracortical inhibition, and cortical silent period. Paired associative stimulation (PAS) was applied to assess LTP-like mechanisms which are mediated through NMDAR. Moreover, resting state functional connectivity was determined using functional magnetic resonance imaging. Results: PAS-induced plasticity differed significantly between groups (P = 0.0056). Cortical excitability, as assessed via motor-evoked potentials after PAS, decreased in patients, whereas it increased in controls indicating malfunctioning of NMDAR in encephalitis patients. Lower PAS-induced plasticity significantly correlated with the modified Rankin Scale (mRS) (r = −0.41; P = 0.0031) and was correlated with lower functional connectivity within the motor network in NMDAR encephalitis patients (P < 0.001, uncorrected). Other neurophysiological parameters were not significantly different between groups. Follow-up assessments were available in six patients and demonstrated parallel improvement of PAS-induced plasticity and mRS. Interpretation: Assessment of PAS-induced plasticity may help to determine NMDAR dysfunction and disease severity in NMDAR encephalitis, and might even aid as a sensitive, noninvasive, and well-tolerated “electrophysiological biomarker” to monitor therapy response in the future.Clinical Trial Registration: ClinicalTrials.gov: Identifier: NCT0186557

On the Maxwell-Stefan approach to multicomponent diffusion

We consider the system of Maxwell-Stefan equations which describe multicomponent diffusive fluxes in non-dilute solutions or gas mixtures. We apply the Perron-Frobenius theorem to the irreducible and quasi-positive matrix which governs the flux-force relations and are able to show normal ellipticity of the associated multicomponent diffusion operator. This provides local-in-time wellposedness of the Maxwell-Stefan multicomponent diffusion system in the isobaric, isothermal case.Comment: Based on a talk given at the Conference on Nonlinear Parabolic Problems in Bedlewo, Mai 200

The ℓs\ell^s-boundedness of a family of integral operators on UMD Banach function spaces

We prove the $\ell^s$-boundedness of a family of integral operators with an operator-valued kernel on UMD Banach function spaces. This generalizes and simplifies earlier work by Gallarati, Veraar and the author, where the $\ell^s$-boundedness of this family of integral operators was shown on Lebesgue spaces. The proof is based on a characterization of $\ell^s$-boundedness as weighted boundedness by Rubio de Francia.Comment: 13 pages. Generalization of arXiv:1410.665

Olfactory and gustatory dysfunction in patients with autoimmune encephalitis

OBJECTIVE: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). METHODS: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). RESULTS: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; r(s) = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. CONCLUSIONS: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results

The impact of the environment on health by country: a meta-synthesis

<p>Abstract</p> <p>Background</p> <p>Health gains that environmental interventions could achieve are main questions when choosing environmental health action to prevent disease. The World Health Organization has recently released profiles of environmental burden of disease for 192 countries.</p> <p>Methods</p> <p>These country profiles provide an estimate of the health impacts from the three major risk factors 'unsafe water, sanitation & hygiene', 'indoor air pollution from solid fuel use' and 'outdoor air pollution'. The profiles also provide an estimate of preventable health impacts by the environment as a whole. While the estimates for the three risk factors are based on country exposures, the estimates of health gains for total environmental improvements are based on a review of the literature supplemented by expert opinion and combined with country health statistics.</p> <p>Results</p> <p>Between 13% and 37% of the countries' disease burden could be prevented by environmental improvements, resulting globally in about 13 million deaths per year. It is estimated that about four million of these could be prevented by improving water, sanitation and hygiene, and indoor and outdoor air alone. The number of environmental DALYs per 1000 capita per year ranges between 14 and 316 according to the country. An analysis by disease group points to main preventions opportunities for each country.</p> <p>Conclusion</p> <p>Notwithstanding the uncertainties in their calculation, these estimates provide an overview of opportunities for prevention through healthier environments. The estimates show that for similar national incomes, the environmental burden of disease can typically vary by a factor five. This analysis also shows that safer water, sanitation and hygiene, and safer fuels for cooking could significantly reduce child mortality, namely by more than 25% in 20 of the lowest income countries.</p

Maximal regularity for non-autonomous equations with measurable dependence on time

In this paper we study maximal $L^p$-regularity for evolution equations with time-dependent operators $A$. We merely assume a measurable dependence on time. In the first part of the paper we present a new sufficient condition for the $L^p$-boundedness of a class of vector-valued singular integrals which does not rely on H\"ormander conditions in the time variable. This is then used to develop an abstract operator-theoretic approach to maximal regularity. The results are applied to the case of $m$-th order elliptic operators $A$ with time and space-dependent coefficients. Here the highest order coefficients are assumed to be measurable in time and continuous in the space variables. This results in an $L^p(L^q)$-theory for such equations for $p,q\in (1, \infty)$. In the final section we extend a well-posedness result for quasilinear equations to the time-dependent setting. Here we give an example of a nonlinear parabolic PDE to which the result can be applied.Comment: Application to a quasilinear equation added. Accepted for publication in Potential Analysi