Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.

Epidemiology, Outcomes, and Associated Factors of Coronavirus Disease 2019 (COVID-19) Reverse Transcriptase Polymerase Chain Reaction-Confirmed Cases in the San Pedro Sula Metropolitan Area, Honduras.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused substantial morbidity and mortality worldwide. Few reports exist in Latin America, a current epicenter of transmission. Here, we aim to describe the epidemiology and outcomes associated with coronavirus disease 2019 (COVID-19) in Honduras. METHODS: Baseline clinical and epidemiological information of SARS-CoV-2 reverse transcriptase polymerase chain reaction-confirmed cases detected between 17 March-4 May in the San Pedro Sula Metropolitan area was collected; for hospitalized cases, clinical data were abstracted. Logistic regression models were fit to determine the factors associated with hospitalization. RESULTS: We identified 877 COVID-19 cases, of which 25% (n = 220) were hospitalized. The 19-44-year age group (57.8%) and males (61.3%) were predominant in overall COVID-19 cases. Of the cases, 34% (n = 299) had at least 1 preexisting medical condition. Individuals aged 45-69 years (adjusted odds ratio [aOR] = 4.05; 95% confidence interval [CI], 2.85-5.76) or ≥70 years (aOR = 9.12; 95% CI, 5.24-15.86), of male sex (aOR = 1.72; 95% CI, 1.21-2.44), and those with a preexisting condition (aOR = 2.12; 95% CI, 1.43-3.14) had higher odds of hospitalization. Of inpatients, 50% were hospitalized more than 7 days. The median length of hospitalization was 13 days (interquartile range [IQR], 8-29) among individuals aged 19-44 years, and 17 days (IQR, 11-24.6) among those aged 45-69. Of the fatal cases, 42% occurred among adults under 60 years old. CONCLUSIONS: Our findings show that a high proportion of COVID-19 cases in Honduras occurred among younger adults, who also constituted a significant proportion of severe and fatal cases. Preexisting conditions were associated with severe outcomes independently from age and were highly prevalent in Honduran COVID-19 cases.

Dynamical Descalarization in Binary Black Hole Mergers.

Scalar fields coupled to the Gauss-Bonnet invariant can undergo a tachyonic instability, leading to spontaneous scalarization of black holes. Studies of this effect have so far been restricted to single black hole spacetimes. We present the first results on dynamical scalarization in head-on collisions and quasicircular inspirals of black hole binaries with numerical relativity simulations. We show that black hole binaries can either form a scalarized remnant or dynamically descalarize by shedding off its initial scalar hair. The observational implications of these findings are discussed.

Astrophysical and Theoretical Physics Implications from Multimessenger Neutron Star Observations.

The Neutron Star Interior Composition Explorer (NICER) recently measured the mass and equatorial radius of the isolated neutron star PSR J0030+0451. We use these measurements to infer the moment of inertia, the quadrupole moment, and the surface eccentricity of an isolated neutron star for the first time, using relations between these quantities that are insensitive to the unknown equation of state of supranuclear matter. We also use these results to forecast the moment of inertia of neutron star A in the double pulsar binary J0737-3039, a quantity anticipated to be directly measured in the coming decade with radio observations. Combining this information with the measurement of the tidal Love number with LIGO/Virgo observations, we propose and implement the first theory-agnostic and equation-of-state-insensitive test of general relativity. Specializing these constraints to a particular modified theory, we find that consistency with general relativity places the most stringent constraint on gravitational parity violation to date, surpassing all other previously reported bounds by 7 orders of magnitude and opens the path for a future test of general relativity with multimessenger neutron star observations.

Spin-Induced Scalarized Black Holes.

It was recently shown that a scalar field suitably coupled to the Gauss-Bonnet invariant G can undergo a spin-induced linear tachyonic instability near a Kerr black hole. This instability appears only once the dimensionless spin j is sufficiently large, that is, j≳0.5. A tachyonic instability is the hallmark of spontaneous scalarization. Focusing, for illustrative purposes, on a class of theories that do exhibit this instability, we show that stationary, rotating black hole solutions do indeed have scalar hair once the spin-induced instability threshold is exceeded, while black holes that lie below the threshold are described by the Kerr solution. Our results provide strong support for spin-induced black hole scalarization.

Square Peg in a Circular Hole: Choosing the Right Ansatz for Isolated Black Holes in Generic Gravitational Theories.

The metric of a spacetime can be greatly simplified if the spacetime is circular. We prove that in generic effective theories of gravity, the spacetime of a stationary, axisymmetric, and asymptotically flat solution must be circular if the solution can be obtained perturbatively from a solution in the general relativity limit. This result applies to a broad class of gravitational theories that include arbitrary scalars and vectors in their light sector, so long as their nonstandard kinetic terms and nonmininal couplings to gravity are treated perturbatively.

Erratum: Fundamental Physics Implications for Higher-Curvature Theories from Binary Black Hole Signals in the LIGO-Virgo Catalog GWTC-1 [Phys. Rev. Lett. 123, 191101 (2019)].

This corrects the article DOI: 10.1103/PhysRevLett.123.191101.

Fundamental Physics Implications for Higher-Curvature Theories from Binary Black Hole Signals in the LIGO-Virgo Catalog GWTC-1.

Gravitational-wave astronomy offers not only new vistas into the realm of astrophysics, but it also opens an avenue for probing, for the first time, general relativity in its strong-field, nonlinear, and dynamical regime, where the theory's predictions manifest themselves in their full glory. We present a study of whether the gravitational-wave events detected so far by the LIGO-Virgo scientific collaborations can be used to probe higher-curvature corrections to general relativity. In particular, we focus on two examples: Einstein-dilaton-Gauss-Bonnet and dynamical Chern-Simons gravity. We find that the two events with a low-mass m≈7 M_{⊙} BH (GW151226 and GW170608) place stringent constraints on Einstein-dilaton-Gauss-Bonnet gravity, α_{EDGB}^{1/2}≲5.6 km, whereas dynamical Chern-Simons gravity remains unconstrained by the gravitational-wave observations analyzed.

Spontaneous Scalarization of Black Holes and Compact Stars from a Gauss-Bonnet Coupling.

We identify a class of scalar-tensor theories with coupling between the scalar and the Gauss-Bonnet invariant that exhibit spontaneous scalarization for both black holes and compact stars. In particular, these theories formally admit all of the stationary solutions of general relativity, but these are not dynamically preferred if certain conditions are satisfied. Remarkably, black holes exhibit scalarization if their mass lies within one of many narrow bands. We find evidence that scalarization can occur in neutron stars as well.

Facial Laxity Rating Scale Validation Study.

BACKGROUND: Age, weight change, clinical or surgical procedures, and distinctive characteristics, combine to be perceived as degrees of flaccidity. There is an absence of a validated scale to accurately assess the firmness-laxity spectrum of the face and neck with accepted classification and terminology. OBJECTIVE: To create a simplified assessment tool to measure the degree of laxity in the face and neck: the Facial Laxity Rating (FLR) scale. METHODS: The FLR scale evaluates 4 distinctive signs (eyelid folds, nasojugal folds, jowls, and neck profile) in 4 regions: upper face, middle face, lower face, and neck. This study incorporated a focused training component for 7 independent physician blinded photograph scorers. A total of 188 ratings were assessed. RESULTS: Combined weighted kappa inter-rater agreement was 0.77 (95% CI, 0.76-0.78) for 188 ratings. Mean inter-rater agreement for laxity class was 0.78 (95% CI, 0.77-0.80). Agreement scoring relative to the truth standard was 92.53% (90.31-94.21), averaged for 7 investigators. CONCLUSION: This study effectively presents the validation of the FLR scale for both inter-rater and agreement relative to the truth standard, demonstrating that the FLR scale may be used as a reliable instrument for quantitative assessment of chronological or treatment related laxity of the face and neck.

Difficult Diagnosis between B Cell Lymphoma and Classical Hodgkin's Lymphoma.

Although primary mediastinal large B-cell lymphoma and classic Hodgkin lymphoma of nodular sclerosis type are distinct disease, they share several clinical characteristics and biologic features. However, there are mediastinal lymphomas that not fit in either category. These types of lymphomas are recognized as mediastinal gray zone lymphomas. Gray zone lymphomas are lymphatic tumors that cannot be assigned to a defined lymphoma entity due to morphological, clinical, or genetic reasons. In this report, we present a case of a 22 year-old-Hispanic-female diagnosed with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Hodgkin lymphoma.

Characterization of cytokinin signaling and homeostasis gene families in two hardwood tree species: Populus trichocarpa and Prunus persica.

BACKGROUND: Through the diversity of cytokinin regulated processes, this phytohormone has a profound impact on plant growth and development. Cytokinin signaling is involved in the control of apical and lateral meristem activity, branching pattern of the shoot, and leaf senescence. These processes influence several traits, including the stem diameter, shoot architecture, and perennial life cycle, which define the development of woody plants. To facilitate research about the role of cytokinin in regulation of woody plant development, we have identified genes associated with cytokinin signaling and homeostasis pathways from two hardwood tree species. RESULTS: Taking advantage of the sequenced black cottonwood (Populus trichocarpa) and peach (Prunus persica) genomes, we have compiled a comprehensive list of genes involved in these pathways. We identified genes belonging to the six families of cytokinin oxidases (CKXs), isopentenyl transferases (IPTs), LONELY GUY genes (LOGs), two-component receptors, histidine containing phosphotransmitters (HPts), and response regulators (RRs). All together 85 Populus and 45 Prunus genes were identified, and compared to their Arabidopsis orthologs through phylogenetic analyses. CONCLUSIONS: In general, when compared to Arabidopsis, differences in gene family structure were often seen in only one of the two tree species. However, one class of genes associated with cytokinin signal transduction, the CKI1-like family of two-component histidine kinases, was larger in both Populus and Prunus than in Arabidopsis.

Cross-cultural perspectives on patient expectations in cosmetic dermatology: A comparative analysis across countries and ethnicities.

Patient expectations in cosmetic dermatology exhibit significant variations across countries, cultures, and ethnicities, thereby reflecting individual desires, concerns, and goals. While some individuals seek aesthetic enhancements, others prioritize addressing specific skin conditions within the context of beauty norms in their respective countries. The provision of personalized and culturally sensitive care plays a crucial role in meeting these diverse expectations. Skin characteristics and concerns differ among ethnicities, influencing treatment preferences. For instance, individuals with darker skin tones may prioritize the treatment of pigmentation disorders, whereas those with lighter skin tones may focus on achieving a fair complexion. Furthermore, differences in facial anatomy among various ethnicities necessitate tailored treatment approaches. This commentary aims to contribute to the effective understanding and management of patient expectations, ultimately leading to satisfactory outcomes. Additional research and regional studies are required to further deepen our understanding of patient expectations in cosmetic dermatology and enable the delivery of improved and culturally appropriate care on a global scale.

Increase of vesicular glutamate transporter 2 co-expression in the deep cerebellar nuclei related to skilled reach learning.

Motor learning induces plasticity in multiple brain regions involving the cerebellum as a crucial player. Synaptic plasticity in the excitatory collaterals to the cerebellar output, the deep cerebellar nuclei (DCN), have recently been shown to be an important part of motor learning. These synapses are composed of climbing fiber (CF) and mossy fiber synapses, with the former conveying unconditioned and the latter conditioned responses in classical conditioning paradigms. The CF synapse on to the cerebellar cortex and the DCN express vesicular transporter 2 (vGluT2), whereas mossy fibers express vGluT1 and /or vGluT2 in their terminals. However, the underlying regulatory mechanism of vGluT expression in the DCN remains unknown. Here we confirm the increase of vGluT2 in a specific part of the DCN during the acquisition of a skilled reaching task in mice. Furthermore, our findings show that this is due to an increase in co-expression of vGluT2 in vGluT1 presynapses instead of the formation of new vGluT2 synapses. Our data indicate that remodeling of synapses - in contrast to synaptogenesis - also plays an important role in motor learning and may explain the presence of both vGluT's in some mossy fiber synapses.

Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer's Disease APP/PS1 Mouse Model.

Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer's disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer's disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.

Learning-related contraction of gray matter in rodent sensorimotor cortex is associated with adaptive myelination.

From observations in rodents, it has been suggested that the cellular basis of learning-dependent changes, detected using structural MRI, may be increased dendritic spine density, alterations in astrocyte volume, and adaptations within intracortical myelin. Myelin plasticity is crucial for neurological function, and active myelination is required for learning and memory. However, the dynamics of myelin plasticity and how it relates to morphometric-based measurements of structural plasticity remains unknown. We used a motor skill learning paradigm in male mice to evaluate experience-dependent brain plasticity by voxel-based morphometry (VBM) in longitudinal MRI, combined with a cross-sectional immunohistochemical investigation. Whole-brain VBM revealed nonlinear decreases in gray matter volume (GMV) juxtaposed to nonlinear increases in white matter volume (WMV) within GM that were best modeled by an asymptotic time course. Using an atlas-based cortical mask, we found nonlinear changes with learning in primary and secondary motor areas and in somatosensory cortex. Analysis of cross-sectional myelin immunoreactivity in forelimb somatosensory cortex confirmed an increase in myelin immunoreactivity followed by a return towards baseline levels. Further investigations using quantitative confocal microscopy confirmed these changes specifically to the length density of myelinated axons. The absence of significant histological changes in cortical thickness suggests that nonlinear morphometric changes are likely due to changes in intracortical myelin for which morphometric WMV in somatosensory cortex significantly correlated with myelin immunoreactivity. Together, these observations indicate a nonlinear increase of intracortical myelin during learning and support the hypothesis that myelin is a component of structural changes observed by VBM during learning.

Predicting the risk of postinflammatory hyperpigmentation: The palmar creases pigmentation scale.

BACKGROUND: Postinflammatory hyperpigmentation (PIH) may affect any skin type but has been linked more often to darker skin. While propensity to hyperpigmentation has not been fully elucidated, there may be a direct correlation to one's palmar crease pigmentation. OBJECTIVE: The aim of this study is to validate the reliable use of a palmar creases pigmentation (PCP) scale, and its accuracy in predicting the risk of PIH. METHODS: A prospective, comparative, and blinded study was conducted through photo-numeric analysis of 126 photographs of pairs of palms. We utilized a 4-point visual scale based on the level of contrast between palmar crease pigment and that of the surrounding skin. Score 0 indicated no difference, score 1 referred to a low difference, score 2 meant a moderate difference, and score 3 related to a high difference. Scores were subdivided based on the risk of PIH. Scores 0-1 are low risk and scores 2-3 are high risk. A panel of 8 medical experts independently evaluated and re-evaluated the photographs that were shown in a random order. RESULTS: A significant degree of inter-rater reliability was found at both evaluation visits, with an intra-class correlation coefficient (ICC) = 0.908, P <.001, at the first evaluation and an ICC = 0.924, P <.001, at the second evaluation, demonstrating a validity of the scale. Global Fleiss kappa for intra-rater reliability for all physicians was 0.514. CONCLUSION: The PCP scale can be effectively used by any physician to predict hyperpigmentation risk.

Prevalencia del consumo de bebidas energizantes y efectos adversos en estudiantes de medicina / Prevalence of energy drinks consumption and adverse effects among medical students

Introducción: las bebidas energizantes son preparados estimulantes e hidratos de carbono. Objetivo: determinar la prevalencia, características del consumo y los efectos adversos en estudiantes de un programa de medicina Metodología: estudio observacional, descriptivo, de corte transversal y retrospectivo, que incluyó estudiantes de medicina de una institución de educación superior, excluyendo a aquellos que no cursaban la carga académica completa para su semestre, quienes diligenciaron de manera inadecuada la encuesta o que no aceptaron la participación en el estudio. Resultados y discusión: participaron 241 estudiantes, de los cuales 72,20% eran mujeres. Solo 55 manifestaron trastornos patológicos de tipo insomnio (13,69%) y cefalea o migraña (8,30%) y 49,38% informaron sobre el consumo de bebidas energizantes. Existe la probabilidad de una mezcla con sustancias alcohólicas dada la elevada frecuencia de consumo (51,26%), lo que no ocurrió con el hábito de fumar. Los eventos adversos informados fueron insomnio (21,58%), taquicardia (17,43%), cefalea (14,52%), enrojecimiento facial (13,28%) y en menor medida temblor, ansiedad o trastornos gastrointestinales (17,42%). Conclusiones: el consumo de bebidas energizantes es alta durante la adolescencia y en especial en los universitarios, pero estas sustancias a largo plazo pueden generar efectos adversos cuyas principales complicaciones son cardíacas, por lo que es importante vigilar la comercialización de las mismas.

Introduction: energy drinks (ED) are stimulant and carbohydrate preparations. Objective: to determine the prevalence, characteristics of ED usage and adverse effects among students of a medical program Methodology: an observational, descriptive, cross-sectional, retrospective study, which included medical students of a higher education institution. Those who were not completing the full academic load for their semester, those who responded the survey inadequately or did not agree to participate in the study, were excluded. Results and discussion: 241 students participated, of which 72,20% were females. Only 55 reported symptoms such as insomnia (13.69%) and headache or migraine (8.30%) and 49.38% reported on ED consumption. To combine energy drinks with alcohol is probable, given the high alcohol consumption rate (51.26%), while it was not associated with smoking. Adverse events reported were insomnia (21.58%), tachycardia (17.43%), headache (14.52%), facial flushing (13.28%) and tremor; and to a lesser extent, anxiety, and gastrointestinal disorders (17.42%). Conclusions: energy drinks consumption is high at adolescence, especially among university students. These preparations can produce long-term adverse effects mainly cardiovascular complications. Thus, monitoring ED marketing is important.

Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD. Recent studies indicate that autophagy may be activated by dopamine D2 and D3 receptor (D2R/D3R) agonists. Since autophagy plays a central role in the degradation of misfolded proteins, and striatal neurons express D2R and D3R, D2R/D3R agonists may promote the clearance of mHTT in striatal neurons. Here, this hypothesis was tested by treating 8-week old R6/1 mice with the D2R/D3R agonist pramipexole for 4weeks. Pramipexole reduced striatal levels of soluble mHTT and increased the size of intranuclear inclusions in R6/1 mice. Furthermore, striatal DARPP-32 levels and motor functions were recovered. These effects were accompanied by an increase in LC3-II and a decrease in p62 in the striatum. Tollip, a selective adaptor of ubiquitinated polyQ proteins to LC3, was also reduced in the striata of R6/1mice but not in their wild-type littermates. No changes were detected in the cerebral cortex where D3R expression is very low, and behavioral and biochemical effects in the striatum were prevented by a D3R antagonist. The findings indicate that PPX protects striatal neurons by promoting the clearance of soluble mHTT through a D3R-mediated mechanism. The evidence of autophagy markers suggests that autophagy is activated, although it is not efficient at removing all mHTT recruited by the autophagic machinery as indicated by the increase in the size of intranuclear inclusions.

Noninvasive submental fat reduction using colder cryolipolysis.

BACKGROUND: Cryolipolysis has shown to significantly reduce localized subcutaneous fat, including submental fat. Temperatures below -11°C have not been used to treat the submental region. OBJECTIVE: The purpose of this study was to evaluate safety and efficacy of Cryolipolysis for noninvasive reduction of submental fat using lower temperatures and reduced treatment time. METHODS: A small volume applicator was used to treat 15 subjects, using a noninvasive tissue cooling device (CoolSculpting System, ZELTIQ Aesthetics, Pleasanton, CA, USA) during 45 and 30 minutes at -12 and -15°C, respectively, to induce reduction of submental fat. Two treatments with an interval of 10 weeks were performed. Adverse events were monitored to assess safety. Treated area was evaluated using digital photography, and caliper measurements prior treatment, 10 weeks after first treatment and 12 weeks after second treatment. All patients were also evaluated before and after 12-week postlast treatment by Magnetic Resonance Imaging (MRI). RESULTS: The mean (SD) reduction measured by skin fold caliper was 33% (3.2 mm [1.7 mm]), (95% CI, 0.2297-0.4236; P=.05), and by MRI, mean (SD) reduction was 1.78 mm (1.157 mm). Independent blinded panel was able to correctly identify 60% of before and after photographs; 12 of 15 subjects (80%) were satisfied or very satisfied with the treatment. Side effects were mild and resolved completely within 10 weeks, except for one hyperpigmentation, which resolved spontaneously within 6 months after last treatment. CONCLUSION: Cryolipolysis with colder temperature and reduced treatment time continues to be effective and is safe for noninvasive reduction of the submental fat.