RESUMEN
The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.
RESUMEN
BACKGROUND AND OBJECTIVES: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) is an emerging technique for the treatment of severe, medication-refractory tremor syndromes. We here report motor and non-motor outcomes 6 and 12 months after unilateral MRgFUS thalamotomy in tremor-dominant Parkinson's disease (tdPD). METHODS: 25 patients with tdPD underwent neuropsychological evaluation including standardized questionnaires of disability, quality of life (QoL), mood, anxiety, apathy, sleep disturbances, and cognition at baseline, 6 and 12 months after MRgFUS. Motor outcome was evaluated using the Clinical Rating Scale for Tremor (CRST) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). In addition, side effects and QoL of family caregivers were assessed. RESULTS: 12 months after MRgFUS significant improvements were evident in the tremor subscores. Patients with concomitant rest and postural tremor showed better tremor outcomes compared to patients with predominant rest tremor. There were no differences in the non-motor assessments. No cognitive decline was observed. Side effects were mostly transient (54%) and classified as mild (62%). No changes in the caregivers' QoL could be observed. CONCLUSION: We found no changes in mood, anxiety, apathy, sleep, cognition or persistent worsening of gait disturbances after unilateral MRgFUS thalamotomy in tdPD. Concomitant postural tremors responded better to treatment than predominant rest tremors.
RESUMEN
Distinct from ovarian estradiol, the steroid hormone 17ß-estradiol (E2) is produced in the brain and is involved in numerous functions, particularly acting as a neurosteroid. However, the physiological role of E2 and the mechanism of its effects are not well known. In hippocampal slices, 17ß-estradiol has been found to cause a modest increase in fast glutamatergic transmission; because some of these effects are rapid and acute, they might be mediated by membrane-associated receptors via nongenomic action. Moreover, activation of membrane estrogen receptors can rapidly modulate neuron function in a sex-specific manner. To further investigate the neurological role of E2, we examined the effect of E2, as an estrogen receptor (ER) agonist, on synaptic transmission in slices of the prefrontal cortex (PFC) and hippocampus in both male and female mice. Whole-cell recordings of spontaneous excitatory postsynaptic currents (sEPSC) in the PFC showed that E2 acts as a neuromodulator in glutamatergic transmission in the PFC in both sexes, but often in a cell-specific manner. The sEPSC amplitude and/or frequency responded to E2 in three ways, namely by significantly increasing, decreasing or having no response. Additional experiments using an agonist selective for ERß, diarylpropionitrile (DPN) showed that in males the sEPSC and spontaneous inhibitory postsynaptic currents sIPSC responses were similar to their E2 responses, but in females the estrogen receptor ß (ERß) agonist DPN did not influence excitatory transmission in the PFC. In contrast, in the hippocampus of both sexes E2 potentiated the gluatmatergic synaptic transmission in a subset of hippocampal cells. These data indicate that activation of E2 targeting probably a estrogen subtypes or different downstream signaling affect synaptic transmission in the brain PFC and hippocampus between males versus females mice.
