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

Delayed recruitment of activity-dependent bulk endocytosis in Fmr1 knockout neurons

The presynapse performs an essential role in brain communication via the activity-dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons. Exploiting a series of optical and morphological assays, we revealed that the majority of nerve terminals displayed activity-dependent calcium influx from 3 days in vitro (DIV), immediately followed by functional evoked exocytosis and endocytosis, although the number of responsive nerve terminals continued to increase until the second week in vitro. However, the most intriguing discovery was that activity-dependent bulk endocytosis (ADBE) was only observed from DIV 14 onwards. Importantly, optimal ADBE recruitment was delayed until DIV 21 in Fmr1 knockout neurons, which model Fragile X Syndrome (FXS). This implicates the delayed recruitment of ADBE as a potential contributing factor in the development of circuit dysfunction in FXS, and potentially other neurodevelopmental disorders. (Figure presented.)</p

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

LAB-AID: an interactive web application for visualization of multi-level data from biological experiments

A key step in understanding the results of biological experiments is visualization of the data. Many laboratory experiments contain a range of measurements that exist within a hierarchy of interdependence. An automated and facile way to visualize and interrogate such multi-level data, across many experimental variables, would: 1) lead to improved understanding of the results, 2) help to avoid misleading interpretation of statistics, and 3) easily identify outliers and sources of batch and confounding effects. While many excellent graphing solutions already exist, they are often geared towards the production of publication-ready plots, the analysis of a single variable at a time, require programming expertise, or are unnecessarily complex for the task at hand. Here we present LAB-AID (Laboratory Automated Interrogation of Data), an interactive tool specifically designed to automatically visualize and query hierarchical data resulting from biological experiment

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

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