Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice.

BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD. METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice. RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes. CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.

Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α.

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate that deletion of the autism spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (NSEPten knockout [KO]) results in robust cortical circuit hyperexcitability selectively in female mice observed as prolonged spontaneous persistent activity states. Circuit hyperexcitability in females is mediated by metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) signaling to mitogen-activated protein kinases (Erk1/2) and de novo protein synthesis. Pten KO layer 5 neurons have a female-specific increase in mGluR5 and mGluR5-dependent protein synthesis. Furthermore, mGluR5-ERα complexes are generally elevated in female cortices, and genetic reduction of ERα rescues enhanced circuit excitability, protein synthesis, and neuron size selectively in NSEPten KO females. Female NSEPten KO mice display deficits in sensory processing and social behaviors as well as mGluR5-dependent seizures. These results reveal mechanisms by which sex and a high-confidence ASD-risk gene interact to affect brain function and behavior.

Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent electroencephalographic (EEG) studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.

Female specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and Estrogen Receptor α.

Autism manifests differently in males and females and the brain mechanisms that mediate these sex-dependent differences are unknown. Here, we demonstrate that deletion of the ASD-risk gene, Pten, in neocortical pyramidal neurons (NSE Pten KO) results in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). Circuit hyperexcitability in NSE Pten KO mice is mediated by enhanced and/or altered signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) to ERK and protein synthesis selectively in Pten deleted female neurons. In support of this idea, Pten deleted Layer 5 cortical neurons have female-specific increases in mGluR5 and mGluR5-driven protein synthesis. In addition, mGluR5-ERα complexes are elevated in female cortex and genetic reduction of ERα in Pten KO cortical neurons rescues circuit excitability, protein synthesis and enlarged neurons selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in female NSE Pten KO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germline Pten +/- mice. Our results reveal molecular mechanisms by which sex and a high impact ASD-risk gene interact to affect brain function and behavior.

Validity and reliability of Squegg device in measuring isometric handgrip strength.

OBJECTIVE: The quantitative measurement of handgrip strength is important in assessing and charting the progress of patients with neuromuscular diseases. The aim of this research was to determine the intra-rater and inter-rater reliability and the validity of the Squegg digital dynamometer. SUBJECTS AND METHODS: Twenty-one females and nine male participants with an age range between 18 and 40 years volunteered for the study. Three testers each took three measurements with a Squegg device and a Jamar dynamometer using standardized measurement techniques. Intra- and inter-tester reliability were calculated using the intra-class correlation coefficient (ICC). To investigate the relationship between hand measures and isometric handgrip strength, the Pearson correlation coefficient test was used. To determine the agreement between the two devices, a Bland Altman plot was constructed, and the concurrent validity of Squegg was calculated. RESULTS: The intra-rater reliability coefficients for both Jamar and Squegg were greater than 0.99 for all three testers, indicating excellent intra-rater reliability. The inter-rater reliability of Jamar (ICC=0.93) and Squegg (ICC=0.87) was excellent. With an ICC of 0.844 and an r-value of 0.720, Squegg with Jamar demonstrates good validity and statistical significance (p=0.001). CONCLUSIONS: The isometric handgrip strength and hand measures showed a moderate correlation in the study population. The Squegg isometric handgrip dynamometer has good concurrent validity and great intra- and inter-rater reliability in healthy individuals. The validity of Squegg in patients with neuromuscular diseases that affect hand function has to be investigated further.

Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome.

BACKGROUND: Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception and language development. Abnormal development of temporal processing may account for the language impairments associated with ASD. Very little is known about the development of temporal processing in any animal model of ASD. METHODS: In the current study, we quantify auditory temporal processing throughout development in the Fmr1 knock-out (KO) mouse model of Fragile X Syndrome (FXS), a leading genetic cause of intellectual disability and ASD-associated behaviors. Using epidural electrodes in awake and freely moving wildtype (WT) and KO mice, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (gap-ASSR) paradigm. Mice were recorded at three different ages in a cross sectional design: postnatal (p)21, p30 and p60. Recordings were obtained from both auditory and frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses to gaps of different widths embedded in noise, providing an objective measure of temporal processing across genotypes and age groups. RESULTS: We present evidence that the frontal, but not auditory, cortex shows significant temporal processing deficits at p21 and p30, with poor ability to phase lock to rapid gaps in noise. Temporal processing was similar in both genotypes in adult mice. ERP amplitudes were larger in Fmr1 KO mice in both auditory and frontal cortex, consistent with ERP data in humans with FXS. CONCLUSIONS: These data indicate cortical region-specific delays in temporal processing development in Fmr1 KO mice. Developmental delays in the ability of frontal cortex to follow rapid changes in sounds may shape language delays in FXS, and more broadly in ASD.

Nicotine reduces age-related changes in cortical neural oscillations without affecting auditory brainstem responses.

Neural oscillations at specific frequency bands are associated with cognitive functions and can identify abnormalities in cortical dynamics. In this study, we analyzed EEG signals recorded from auditory and frontal cortex of awake mice across young, middle and old ages, and found multiple robust and novel age-related changes in cortical oscillations. Notably, resting, evoked, and induced gamma power diminished with age, with some changes observed even in the middle age groups. Inter-trial phase coherence of responses to time-varying stimuli is reduced in old mice. Movement-related modulation of gamma power is reduced in old mice. An acute injection of nicotine (0.5 mg/kg), but not saline, in old mice partially or fully reversed the age-related changes in EEG responses. Nicotine had no effect on auditory brainstem responses , suggesting the effects occur more centrally. The age-related changes are consistent with reduced activation of specific inhibitory interneuron subtypes. Importantly, our data suggest that the auditory circuits that generate 'young' responses to sounds are present in old mice, and can be activated by nicotine.

Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. METHODS: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). RESULTS: In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. CONCLUSIONS: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. TRIAL REGISTRATION: The human experiments are registered under NCT02998151.

Production of medium-sized chitosan oligomers using molecular sieves and their antibacterial activity.

Chitosan, derived from the natural polysaccharide chitin, was fragmented in very dilute acetic acid solutions using zeolites and molecular sieves, a type of zeolites, under variable reaction conditions of temperature, acid concentration, duration of reaction, and zeolites of variable pore sizes. Fragmentation resulted in the formation of appreciable amounts of chitosan oligomers comprised of 4-8 units, which were studied by using LC-MS, MS, as well as IR spectroscopy. The prepared fragments were tested for their biological activity and some of them showed antibacterial activity against Gram-positive bacteria.

Neural responses to pup calls and pup odors in California mouse fathers and virgin males.

The onset of mammalian maternal care is associated with plasticity in neural processing of infant-related sensory stimuli; however, little is known about sensory plasticity associated with fatherhood. We quantified behavioral and neural responses of virgin males and new fathers to olfactory and auditory stimuli from young, unfamiliar pups in the biparental California mouse (Peromyscus californicus). Each male was exposed for 10 min to one of four combinations of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Behavior did not differ between fathers and virgins during exposure to sensory stimuli or during the following hour; however, males in both groups were more active both during and after exposure to pup-related stimuli compared to control stimuli. Fathers had lower expression of Fos in the main olfactory bulbs (MOB) but higher expression in the medial preoptic area (MPOA) and bed nucleus of the stria terminalis medial division, ventral part (STMV) compared to virgins. Lastly, males had higher Fos expression in MPOA when exposed to pup odor compared to control stimuli, and when exposed to pup odor and pup calls compared to pup calls only or control stimuli. These findings suggest that the onset of fatherhood alters activity of MOB, MPOA and STMV and that pup odors and vocalizations have additive or synergistic effects on males' behavior and MPOA activation.

Functional consequences of postnatal interventions in a mouse model of Fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is a leading genetic cause of autism and intellectual disability with cortical hyperexcitability and sensory hypersensitivity attributed to loss and hypofunction of inhibitory parvalbumin-expressing (PV) cells. Our studies provide novel insights into the role of excitatory neurons in abnormal development of PV cells during a postnatal period of inhibitory circuit refinement. METHODS: To achieve Fragile X mental retardation gene (Fmr1) deletion and re-expression in excitatory neurons during the postnatal day (P)14-P21 period, we generated CreCaMKIIa/Fmr1Flox/y (cOFF) and CreCaMKIIa/Fmr1FloxNeo/y (cON) mice, respectively. Cortical phenotypes were evaluated in adult mice using biochemical, cellular, clinically relevant electroencephalogram (EEG) and behavioral tests. RESULTS: We found that similar to global Fmr1 KO mice, the density of PV-expressing cells, their activation, and sound-evoked gamma synchronization were impaired in cOFF mice, but the phenotypes were improved in cON mice. cOFF mice also showed enhanced cortical gelatinase activity and baseline EEG gamma power, which were reduced in cON mice. In addition, TrkB phosphorylation and PV levels were lower in cOFF mice, which also showed increased locomotor activity and anxiety-like behaviors. Remarkably, when FMRP levels were restored in only excitatory neurons during the P14-P21 period, TrkB phosphorylation and mouse behaviors were also improved. CONCLUSIONS: These results indicate that postnatal deletion or re-expression of FMRP in excitatory neurons is sufficient to elicit or ameliorate structural and functional cortical deficits, and abnormal behaviors in mice, informing future studies about appropriate treatment windows and providing fundamental insights into the cellular mechanisms of cortical circuit dysfunction in FXS.

Age-related changes in event related potentials, steady state responses and temporal processing in the auditory cortex of mice with severe or mild hearing loss.

Age-related changes in auditory processing affect the quality of life of older adults with and without hearing loss. To distinguish between the effects of sensorineural hearing loss and aging on cortical processing, the main goal of the present study was to compare cortical responses using the same stimulus paradigms and recording conditions in two strains of mice (C57BL/6J and FVB) that differ in the degree of age-related hearing loss. Electroencephalogram (EEG) recordings were obtained from freely moving young and old mice using epidural screw electrodes. We measured event related potentials (ERP) and 40 Hz auditory steady-state responses (ASSR). We used a novel stimulus, termed the gap-ASSR stimulus, which elicits an ASSR by rapidly presenting short gaps in continuous noise. By varying the gap widths and modulation depths, we probed the limits of temporal processing in young and old mice. Temporal fidelity of ASSR and gap-ASSR responses were measured as phase consistency across trials (inter-trial phase clustering; ITPC). The old C57 mice, which show severe hearing loss, produced larger ERP amplitudes compared to young mice. Despite robust ERPs, the old C57 mice showed significantly diminished ITPC in the ASSR and gap-ASSR responses, even with 100% modulation depth. The FVB mice, which show mild hearing loss with age, generated similar ERP amplitudes and ASSR ITPC across the age groups tested. However, the old FVB mice showed decreased gap-ASSR responses compared to young mice, particularly for modulation depths <100%. The C57 mice data suggest that severe presbycusis leads to increased gain in the auditory cortex, but with reduced temporal fidelity. The FVB mice data suggest that with mild hearing loss, age-related changes in temporal processing become apparent only when tested with more challenging sounds (shorter gaps and shallower modulation).

Neural Correlates of Auditory Hypersensitivity in Fragile X Syndrome.

The mechanisms underlying the common association between autism spectrum disorders (ASD) and sensory processing disorders (SPD) are unclear, and treatment options to reduce atypical sensory processing are limited. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and ASD behaviors. As in most children with ASD, atypical sensory processing is a common symptom in FXS, frequently manifesting as sensory hypersensitivity. Auditory hypersensitivity is a highly debilitating condition in FXS that may lead to language delays, social anxiety and ritualized repetitive behaviors. Animal models of FXS, including Fmr1 knock out (KO) mouse, also show auditory hypersensitivity, providing a translation relevant platform to study underlying pathophysiological mechanisms. The focus of this review is to summarize recent studies in the Fmr1 KO mouse that identified neural correlates of auditory hypersensitivity. We review results of electroencephalography (EEG) recordings in the Fmr1 KO mice and highlight EEG phenotypes that are remarkably similar to EEG findings in humans with FXS. The EEG phenotypes associated with the loss of FMRP include enhanced resting EEG gamma band power, reduced cross frequency coupling, reduced sound-evoked synchrony of neural responses at gamma band frequencies, increased event-related potential amplitudes, reduced habituation of neural responses and increased non-phase locked power. In addition, we highlight the postnatal period when the EEG phenotypes develop and show a strong association of the phenotypes with enhanced matrix-metalloproteinase-9 (MMP-9) activity, abnormal development of parvalbumin (PV)-expressing inhibitory interneurons and reduced formation of specialized extracellular matrix structures called perineuronal nets (PNNs). Finally, we discuss how dysfunctions of inhibitory PV interneurons may contribute to cortical hyperexcitability and EEG abnormalities observed in FXS. Taken together, the studies reviewed here indicate that EEG recordings can be utilized in both pre-clinical studies and clinical trials, while at the same time, used to identify cellular and circuit mechanisms of dysfunction in FXS. New therapeutic approaches that reduce MMP-9 activity and restore functions of PV interneurons may succeed in reducing FXS sensory symptoms. Future studies should examine long-lasting benefits of developmental vs. adult interventions on sensory phenotypes.

Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice.

BACKGROUND: Individuals with Fragile X syndrome (FXS) and autism spectrum disorder (ASD) exhibit an array of symptoms, including sociability deficits, increased anxiety, hyperactivity, and sensory hyperexcitability. It is unclear how endocannabinoid (eCB) modulation can be targeted to alleviate neurophysiological abnormalities in FXS as behavioral research reveals benefits to inhibiting cannabinoid (CB) receptor activation and increasing endocannabinoid ligand levels. Here, we hypothesize that enhancement of 2-arachidonoyl-sn-glycerol (2-AG) in Fragile X mental retardation 1 gene knock-out (Fmr1 KO) mice may reduce cortical hyperexcitability and behavioral abnormalities observed in FXS. METHODS: To test whether an increase in 2-AG levels normalized cortical responses in a mouse model of FXS, animals were subjected to electroencephalography (EEG) recording and behavioral assessment following treatment with JZL-184, an irreversible inhibitor of monoacylglycerol lipase (MAGL). Assessment of 2-AG was performed using lipidomic analysis in conjunction with various doses and time points post-administration of JZL-184. Baseline electrocortical activity and evoked responses to sound stimuli were measured using a 30-channel multielectrode array (MEA) in adult male mice before, 4 h, and 1 day post-intraperitoneal injection of JZL-184 or vehicle. Behavior assessment was done using the open field and elevated plus maze 4 h post-treatment. RESULTS: Lipidomic analysis showed that 8 mg/kg JZL-184 significantly increased the levels of 2-AG in the auditory cortex of both Fmr1 KO and WT mice 4 h post-treatment compared to vehicle controls. EEG recordings revealed a reduction in the abnormally enhanced baseline gamma-band power in Fmr1 KO mice and significantly improved evoked synchronization to auditory stimuli in the gamma-band range post-JZL-184 treatment. JZL-184 treatment also ameliorated anxiety-like and hyperactivity phenotypes in Fmr1 KO mice. CONCLUSIONS: Overall, these results indicate that increasing 2-AG levels may serve as a potential therapeutic approach to normalize cortical responses and improve behavioral outcomes in FXS and possibly other ASDs.

Prevalencia de paperas en Bagdad. Irak - 2015 y 2016 / Prevalence of Mumps in Baghdad, Iraq - 2015 & 2016

Antecedentes: las paperas son una infección viral que se transmite por contacto directo, gotitas y fómites. Irak es testigo de varias epidemias de paperas. Objetivo: Informar sobre la última epidemia de paperas 2015-2016. Métodos: El lado de Bagdad de Al-Rusafa fue seleccionado al azar de dos lados de Bagdad. Se llevó a cabo una revisión de los datos del Departamento de Salud Pública de la Dirección de Salud de Bagdad / Al-Rusafa. Los datos fueron todos los casos notificados de paperas para los años 2015-2016. Resultados: Los casos registrados de paperas fueron 9780 y 33728 para 2015 y 2016, respectivamente. La edad máxima en 2015 y 2016 fue de 5 a 14 años. Los picos de casos de paperas se registraron en octubre, diciembre de 2015 y enero de 2016, y desaparecieron en junio de 2016. Conclusiones: La epidemia de paperas fue clara en Bagdad. La lucha social juega un papel en el desarrollo de la epidemia.

Background: Mumps is a viral infection transmitted by direct contact, droplet infection and fomites. Iraq witnesses several epidemics of mumps. Objective: To report on last epidemic of mumps 2015- 2016. Methods: Al-Rusafa side of Baghdad was selected randomly from two sides of Baghdad. A review of data from department of public health, Directorate of Health of Baghdad / Al-Rusafa was carried out. The data was all the notification cases of mumps for the years 2015-2016. Results: The registered cases of mumps were 9780 and 33728 for 2015 and 2016, respectively. The peak age in 2015 and 2016 was 5-14 year. The peaks mumps cases were in October, December 2015 and January 2016, and disappear in June 2016. Conclusions: Epidemic of mumps was clear in Baghdad. Social strife plays a role in developing the epidemic.

Acute ischaemia of the upper limb following peripherally inserted central catheter-a venous to arterial complication cascade.

Peripherally inserted central catheters (PICC) are useful access devices that allow for longer-term intravenous access. This allows patients requiring an extended period of intravenous medication to have this administered without the need for repeat vascular punctures. Even minimally invasive procedures such as line insertion come with risks. Of particular interest to this article is a limb threatening complication soon after line placement. We discuss the PICC line catheter tip as the likely cause for arrhythmia that lead to an embolic occlusion of an upper limb and required acute surgical intervention for limb salvage. We stress the rapid sequence of events that lead to this ultimate complication. We also stress the importance for all clinicians to be aware of these risks and take a cautious approach as the majority of patients requiring longer-term access are already at greater risks of thromboembolic disease due to their comorbidities.

Punicalagin and zinc (II) ions inhibit the activity of SARS-CoV-2 3CL-protease in vitro.

OBJECTIVE: Coronavirus 2019 (COVID-19) has now been declared as a worldwide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any antiviral drugs that will treat COVID-19. Coronaviruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. In this study, we demonstrated that punicalagin, the fundamental active element of pomegranate in addition to the combination of punicalagin with zinc (Zn) II, appear to show powerful inhibitory activity against SARS-CoV-2. MATERIALS AND METHODS: The 3CL protease assay kit was used to quantify 3CL protease action. The tetrazolium dye, MTS, was used to evaluate cytotoxicity. RESULTS: Punicalagin showed inhibitory action against the 3CL-protease in a dose-dependent manner, and IC50 was found to be 6.192 µg/ml for punicalagin. Punicalagin (10 µg/mL) demonstrated a significant inhibitory activity toward 3CL-protease activity (p < 0.001), yet when punicalagin is combined with zinc sulfate monohydrate (punicalagin/Zn-II) extremely strong 3CL-protease activity (p < 0.001) was obtained. The action of 3CL-protease with punicalagin/Zn-II was decreased by approximately 4.4-fold in contrast to only punicalagin (10 µg/mL). Likewise, we did not notice any significant cytotoxicity caused by punicalagin, Zn-II, or punicalagin/Zn-II. CONCLUSIONS: We suggest that these compounds could be used as potential antiviral drugs against COVID-19.

Primary brachial artery aneurysm with associated basilic vein aneurysm.

There are but a handful of reported brachial artery aneurysms, the majority of which are pseudoaneurysms or false aneurysms caused by trauma or fistula creation. True or primary brachial artery aneurysms are even more rare, and if they occur, they often do so in isolation. In this case report, we discuss the interesting finding of a large primary brachial aneurysm together with an adjacent aneurysmal basilic vein identified intra-operatively. This presentation was 21 years after the renal transplant and ligation of an arteriovenous fistula in that same arm. It is noteworthy that the fistula was in the forearm and far away from the site of the untouched brachial area.

Minocycline Treatment Reverses Sound Evoked EEG Abnormalities in a Mouse Model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult Fmr1 KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the Fmr1 KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the Fmr1 KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in Fmr1 KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in Fmr1 KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.