Kaposi's sarcoma in a patient with erythroblastopenia and thymoma: Reactivation after topical corticosteroids

We report a 69-year-old female with erythroblastopenia and thymoma who developed lesions of Kaposi's sarcoma (KS) after thymectomy, 2 months after the initiation of therapy with methylprednisolone. Control of mucocutaneous KS lesions was obtained with radiotherapy, interferon alfa-2b and withdrawal of systemic immunosuppressive therapy. Erosive oral lichen planus appeared later, and after therapy with topical corticosteroids a new lesion of KS developed that regressed after withdrawal of topical corticosteroids. The detection of HHV-8 only in lesional skin supports the hypothesis that this virus can trigger the development of KS lesions

FMRP sustains presynaptic function via control of activity-dependent bulk endocytosis

Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from male Fmr1 knock-out (KO) rats display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 KO neurons to sustain SV recycling during trains of high-frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in KO neurons, however this dysfunction was corrected by BK channel agonists. Therefore, FMRP performs a key role in sustaining neurotransmitter release via selective control of ADBE, suggesting intervention via this endocytosis mode may correct the hyperexcitability observed in FXS. SIGNIFICANCE STATEMENT Loss of fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), however whether its loss has a direct role in neurotransmitter release remains a matter of debate. We demonstrate that neurons lacking FMRP display a specific defect in a mechanism that sustains neurotransmitter release during intense neuronal firing, called activity-dependent bulk endocytosis (ADBE). This discovery provides key insights into mechanisms of brain communication that occur because of loss of FMRP function. Importantly it also reveals ADBE as a potential therapeutic target to correct the circuit hyperexcitability observed in FXS

Epilepsy-related CDKL5 deficiency slows synaptic vesicle endocytosis in central nerve terminals

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from de novo mutations in the X-linked CDKL5 gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from Cdkl5 knockout rat males. Using a genetically encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis. We showed that CDKL5 kinase activity is both necessary and sufficient for optimal SV endocytosis, since kinase-inactive mutations failed to correct endocytosis in Cdkl5 knockout neurons, whereas the isolated CDKL5 kinase domain fully restored SV endocytosis kinetics. Finally, we demonstrated that CDKL5-mediated phosphorylation of amphiphysin 1, a putative presynaptic target, is not required for CDKL5-dependent control of SV endocytosis. Overall, our findings reveal a key presynaptic role for CDKL5 kinase activity and enhance our insight into how its dysfunction may culminate in CDD. SIGNIFICANCE STATEMENT Loss of cyclin-dependent kinase like 5 (CDKL5) function is a leading cause of monogenic childhood epileptic encephalopathy. However, information regarding its biological role is scarce. In this study, we reveal a selective presynaptic role for CDKL5 in synaptic vesicle endocytosis and that its protein kinase activity is both necessary and sufficient for this role. The isolated protein kinase domain is sufficient to correct this loss of function, which may facilitate future gene therapy strategies if presynaptic dysfunction is proven to be central to the disorder. It also reveals that a CDKL5-specific substrate is located at the presynapse, the phosphorylation of which is required for optimal SV endocytosis. </p

Self-perceived oral health and orofacial aesthetics of cleft patients

Purpose: To evaluate the self-perceived oral health and aesthetics of the dentition and jaw in patients with different types of oral cleft, measured by patient-reported outcome measures (PROMs). Additionally, to compare the results of the PROMs between cleft lip and or/palate (CL/P) patients and non-affected controls. Methods: 420 CL/P patients treated at the cleft team of the Erasmus Medical Center, Rotterdam, The Netherlands, were included, and 138 non-cleft patients were recruited as control-group. Patient’s perceptions were retrospectively evaluated using the CLEFT-Q Teeth for dental aesthetics at ages 8, 12 and 22, CLEFT-Q Jaw for jaw aesthetics at ages 12 and 22, and the Child Oral Health Impact Profile—Oral Symptoms Subscale (COHIP-OSS) for oral health at ages 8 and 12. One-way ANOVA was used to compare differences in oral health and aesthetic perceptions among age-groups, cleft types, as well as between cases and controls. Results: CL/P patients were significantly less satisfied than controls with their dental aesthetics (p = 0.001). CL/P patients reported significantly lower satisfaction on CLEFT-Q Teeth scores at ages 8 and 12, than at 22 years (p &lt; 0.001). Patients with the most extensive cleft phenotype, Cleft Lip and Palate (CLAP), reported lowest satisfaction on the CLEFT-Q Teeth. No differences in perceptions of oral health nor in aesthetics of the jaw were found in the different cleft types, ages, nor in study versus control group. Conclusion: This study found differences in self-perceived dental aesthetics: CL/P patients are less satisfied than non-affected controls. CLAP patients are least satisfied, but satisfaction increases with age.</p

Dynamical elastic bodies in Newtonian gravity

Well-posedness for the initial value problem for a self-gravitating elastic body with free boundary in Newtonian gravity is proved. In the material frame, the Euler-Lagrange equation becomes, assuming suitable constitutive properties for the elastic material, a fully non-linear elliptic-hyperbolic system with boundary conditions of Neumann type. For systems of this type, the initial data must satisfy compatibility conditions in order to achieve regular solutions. Given a relaxed reference configuration and a sufficiently small Newton's constant, a neigborhood of initial data satisfying the compatibility conditions is constructed

Mitochondrial genomes of giant deers suggest their late survival in Central Europe

The giant deer Megaloceros giganteus is among the most fascinating Late Pleistocene Eurasian megafauna that became extinct at the end of the last ice age. Important questions persist regarding its phylogenetic relationship to contemporary taxa and the reasons for its extinction. We analyzed two large ancient cervid bone fragments recovered from cave sites in the Swabian Jura (Baden-Württemberg, Germany) dated to 12,000 years ago. Using hybridization capture in combination with next generation sequencing, we were able to reconstruct nearly complete mitochondrial genomes from both specimens. Both mtDNAs cluster phylogenetically with fallow deer and show high similarity to previously studied partial Megaloceros giganteus DNA from Kamyshlov in western Siberia and Killavullen in Ireland. The unexpected presence of Megaloceros giganteus in Southern Germany after the Ice Age suggests a later survival in Central Europe than previously proposed. The complete mtDNAs provide strong phylogenetic support for a Dama-Megaloceros clade. Furthermore, isotope analyses support an increasing competition between giant deer, red deer, and reindeer after the Last Glacial Maximum, which might have contributed to the extinction of Megaloceros in Central Europe

Selective vulnerability of inhibitory networks in multiple sclerosis.

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments

First and Second Order Perturbations of Hypersurfaces

In this paper we find the first and second order perturbations of the induced metric and the extrinsic curvature of a non-degenerate hypersurface $\Sigma$ in a spacetime $(M,g)$, when the metric $g$ is perturbed arbitrarily to second order and the hypersurface itself is allowed to change perturbatively (i.e. to move within spacetime) also to second order. The results are fully general and hold in arbitrary dimensions and signature. An application of these results for the perturbed matching theory between spacetimes is presented.Comment: 31 pages, no figures. To be published in Classical and Quantum Gravit

Evaluation of the Water Film Weber Number in Glaze Icing Scaling

Icing scaling tests were performed in the NASA Glenn Icing Research Tunnel to evaluate a new scaling method, developed and proposed by Feo for glaze icing, in which the scale liquid water content and velocity were found by matching reference and scale values of the nondimensional water-film thickness expression and the film Weber number. For comparison purpose, tests were also conducted using the constant We(sub L) method for velocity scaling. The reference tests used a full-span, fiberglass, 91.4-cm-chord NACA 0012 model with velocities of 76 and 100 knot and MVD sizes of 150 and 195 microns. Scale-to-reference model size ratio was 1:2.6. All tests were made at 0deg AOA. Results will be presented for stagnation point freezing fractions of 0.3 and 0.5

How do Zimbabweans value health states?

Background Quality of life weights based on valuations of health states are often used in cost utility analysis and population health measures. This paper reports on an attempt to develop quality of life weights within the Zimbabwe context. Methods 2,384 residents in randomly selected small residential plots of land in a high-density suburb of Harare valued descriptors of 38 health states based on different combinations of the five domains of the EQ-5D (mobility, self-care, usual activities, pain or discomfort and anxiety or depression). The English version of the EQ-5D was used. The time trade-off method was used to determine the values, and 19,020 individual preferences for health states were analysed. A residual maximum likelihood linear mixed model was used to estimate a function for predicting the values of all possible combinations of levels on the five domains. The model was fit to a random subset of two-thirds of the observations, with the remaining observations reserved for analysis of predictive validity. The results were compared to a similar study undertaken in the United Kingdom. Results A credible model was developed to predict the values of states that were not valued directly. In the subset of observations reserved for validation, the mean absolute difference between predicted and observed values was 0.045. All domains of the EQ-5D were found to contribute significantly to the model, both at the moderate and severe levels. Severe pain was found to have the largest negative coefficient, followed by the inability to wash and dress oneself. Conclusion Despite a generally lower education level than their European counterparts, urban Zimbabweans appear to value health states in a consistent manner, and the determination of a global method of establishing quality of life weights may be feasible and valid. However, as the relative weightings of the different domains, although correlated, differed from the standard set of weights recommended by the EuroQol Group, the locally determined coefficients should be used within the Zimbabwean context