Altered ventilatory responses to hypercapnia-hypoxia challenges in a preclinical SUDEP model involve orexin neurons.

Failure to recover from repeated hypercapnia and hypoxemia challenges caused by severe GCS and postictal apneas may contribute to sudden unexpected death in epilepsy (SUDEP). Our previous studies found orexinergic dysfunction contributes to respiratory abnormalities in a preclinical model of SUDEP, Kcna1-/-mice. Here, we developed two gas challenges consisting of repeated HH exposures and used wholebody plethysmography to determine whether Kcna1-/-mice would have detrimental ventilatory responses. Kcna1-/- mice exhibited an elevated ventilatory response to a mild repeated hypercapnia-hypoxia (HH) challenge compared to WT. Moreover, 71% of Kcna1-/- mice failed to survive a severe repeated HH challenge, whereas all WT mice recovered. We next determined whether orexin was involved in these differences. Pretreatment of Kcna1-/- mice with a dual orexin receptor antagonist rescued the ventilatory response during the mild challenge and all subjects survived the severe challenge. In ex vivo extracellular recordings in the lateral hypothalamus of coronal brain slices, we found reducing pH either inhibits or stimulates putative orexin neurons similar to other chemosensitive neurons; however, a significantly greater percentage of putative orexin neurons from Kcna1-/-mice were stimulated and the magnitude of stimulation was increased resulting in augmentation of the calculated chemosensitivity index relative to WT. Collectively, our data suggest that increased chemosensitive activity of orexin neurons may be pathologic in the Kcna1-/- mouse model of SUDEP, and contribute to elevated ventilatory responses. Our data suggest that individuals at high risk for SUDEP may be more sensitive to HH challenges, whether induced by seizures or other means; and the depth and length of the HH exposure could dictate the probability of survival.

Case report: "Fur stole and turtleneck" and "halter-back" signs: an expanded wardrobe for dermatomyositis.

A diagnosis of dermatomyositis requires recognition of distinct patterns of skin disease in combination with, and sometimes without, muscle weakness. Often, a striking contrast between involved and uninvolved areas is observed. Familiar patterns include eyelid and midfacial eruptions, Gottron papules/sign, and upper back (shawl sign), central chest (V/open collar sign), and lateral thigh (holster sign) involvement. More recently, new specific antibody/phenotype-associated patterns have been reported. We describe a case series of two distinct patterns of skin involvement in six adult patients with both classical and amyopathic dermatomyositis. Three had paraneoplastic disease. All had intermediate to richly pigmented skin; five were of Afro-Caribbean and one was of Asian-Caribbean descent. Four were men, and two were women. Ages ranged from 41 to 89 years. All patients had concomitant hallmark signs (facial, hand, and/or trunk signs). Three were amyopathic. The first pattern involved a sharply demarcated, horizontally oriented hyperpigmented patch/thin plaque across the shoulders and upper chest, extending up the anterior neck. The second was the combination of the classical upper back shawl distribution with distinct mid-back sparing and diffuse involvement of the lower back. Named patterns help with the recognition of skin rashes in dermatomyositis. Based on the current lexicon describing items of apparel, we liken the first pattern to a "fur stole and turtleneck" sign and the latter to a "halter-back" or "reflected-shawl" sign. Biopsies revealed hyperkeratosis and interface dermatitis, often with epidermal atrophy, compatible with dermatomyositis. These patterns perhaps represent the coalescence of already well-described signs, photo-exacerbation, koebnerization, mechanical stretch, and other currently unclear factors contributing to patterning in dermatomyositis. Pattern distribution recognition is particularly valuable in individuals with richly pigmented skin who may lack typical violaceous erythema. The distinct demarcation led to the initial misdiagnosis of allergic contact dermatitis or other exogenous dermatitis in most of our patients. Further work involves evaluation of antibody phenotype and internal involvement associations. Limitations include lack of specific antibody panels and longitudinal follow-up data.

Personalization of SUDEP risk: A survey of transient subclinical comorbid changes.

OBJECTIVE: Preclinical data report within subject modifiable ailments emerge weeks prior to SUDEP, including sleep disorders and cardiorespiratory changes; findings which support anecdotal clinical data. Here, we bridge preclinical findings with future clinical/preclinical studies, and survey whether caretakers or family members of victims noticed transient changes prior to SUDEP. The aim of this pilot study is to identify potential modifiable changes that may synergistically increase SUDEP risk for future research. METHODS: A mobile electronic survey was posted on SUDEP community websites. The survey queried whether changes in seizures, sleep, physical well-being, emotional well-being, cognition, breathing, or heart rate were noticed before SUDEP. RESULTS: The most profound finding was that 85% of victims had multiple transient ailments prior to SUDEP. Changes in seizures (28/54), and sleep (30/58) occurred in more than 50% of the victims and represent the most influential changes identified. The second and third most influential changes were a reduction in physical well-being (25/57) and emotional well-being (26/56). Changes were observed within the last two months of life in approximately one third of the cases, and more than four months prior to SUDEP in approximately one third of cases, indicating a potential time frame for proactive preventative strategies. Respondents also noted changes in cognition (16/55), breathing (9/54) or heart rate (8/55). Data indicate these changes may be associated with increased SUDEP risk within subject. Study limitations include the responses were based on memory, there was a potential for data to be over reported, and caretakers were not prompted to observe changes a priori, thus some existing changes may have gone unnoticed. SIGNIFICANCE: Data support the preclinical findings that transient, subclinical (i.e., not severe enough to require medical intervention), modifiable ailments may increase risk of SUDEP. This suggests that just as an epilepsy type can change over a lifetime and epilepsy type-specific treatments can reduce SUDEP risk, further personalization of SUDEP risk will improve our understanding as to whether variables contribute to risk differently across lifespan. Thus, with a dynamic capacity to change, differing factors may contribute to the distribution of risk probability within an individual at any given time. Understanding whether different combinations of transient changes are specific to epilepsy type, age, or sex needs to be determined to move the field forward in hopes of developing a personalized approach to preventative strategies.

Divergent patterns of zooplankton connectivity in the epipelagic and mesopelagic zones of the eastern North Pacific.

Due to historical under-sampling of the deep ocean, the distributional ranges of mesopelagic zooplankton are not well documented, leading to uncertainty about the mechanisms that shape midwater zooplankton community composition. Using a combination of DNA metabarcoding (18S-V4 and mtCOI) and trait-based analysis, we characterized zooplankton diversity and community composition in the upper 1000 m of the northeast Pacific Ocean. We tested whether the North Pacific Transition Zone is a biogeographic boundary region for mesopelagic zooplankton. We also tested whether zooplankton taxa occupying different vertical habitats and exhibiting different ecological traits differed in the ranges of temperature, Chl-a, and dissolved oxygen conditions inhabited. The depth of the maximum taxonomic richness deepened with increasing latitude in the North Pacific. Community similarity in the mesopelagic zone also increased in comparison with the epipelagic zone, and no evidence was found for a biogeographic boundary between previously delineated mesopelagic biogeochemical provinces. Epipelagic zooplankton exhibited broader temperature and Chl-a ranges than mesopelagic taxa. Within the epipelagic, taxa with broader temperature and Chl-a ranges also had broader distributional ranges. However, mesopelagic taxa were distributed across wider dissolved oxygen ranges, and within the mesopelagic, only oxygen ranges covaried with distributional ranges. Environmental and distributional ranges also varied among traits, both for epipelagic taxa and mesopelagic taxa. The strongest differences in both environmental and distributional ranges were observed for taxa with or without diel vertical migration behavior. Our results suggest that species traits can influence the differential effects of physical dispersal and environmental selection in shaping biogeographic distributions.

Orexin receptors regulate hippocampal sharp wave-ripple complexes in ex vivo slices.

Orexin is a neuromodulatory peptide produced by lateral hypothalamic orexin neurons and binds to G-protein-coupled orexin-1 receptor and orexin-2 receptors. Whether orexin modulates learning and memory is not fully understood. Orexin has biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting at supra- and sub-homeostatic levels. Hippocampal sharp wave-ripples encode memory information and are essential for memory consolidation and retrieval. The role of orexin on sharp wave-ripples in hippocampal CA1 remains unknown. Here, we used multi-electrode array recordings in acute ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on sharp wave-ripples. Bath-application of either the orexin-1 receptor antagonist N-(2-Methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB-334867) or the orexin-2 receptor antagonist N-Ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA) reduced sharp wave and ripple incidence, sharp wave amplitude, and sharp wave duration. SB-334867 and EMPA effects on sharp wave amplitude and duration were equivalent, whereas EMPA exhibited a greater reduction of sharp wave and ripple incidence. EMPA also increased ripple duration, whereas SB-334867 had no effect. Inhibition of both orexin receptors with a dual orexin receptor antagonist N-[1,1'-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2-yl)thio]acetyl-2-pyrrolidinedicarboxamide (TCS-1102) had effects similar to EMPA, however, sharp wave amplitude and duration were unaffected. Region-specific expression of orexin receptors suggests orexin may regulate sharp wave generation in CA3, dentate gyrus-mediated sharp wave modification, sharp wave propagation to CA1, and local ripple emergence in CA1. Our study indicates an orexin contribution to hippocampal sharp wave-ripple complexes and suggests a mechanism by which sub-homeostatic concentrations of orexin may inhibit learning and memory function.

Generalized Essential Telangiectasia.

This case report describes symmetrically distributed red to violaceous fine telangiectasias in a lacelike pattern on the dorsal feet and ankles.

Characterizing Outcomes of Medial and Lateral Perforators in Deep Inferior Epigastric Perforator Flaps.

BACKGROUND: Perforators are typically found in rows in the deep inferior epigastric perforator (DIEP) flap. As methods to assess flap perfusion continue to improve, surgeons may be more likely to select perforators traditionally avoided. The purpose of this article is to describe clinical outcomes based on row and number of perforators to reevaluate flap and abdominal donor site morbidity. METHODS: A retrospective analysis was performed on patients who underwent breast reconstruction with DIEP flaps by four microsurgeons from 2013 to 2020. The row and number of perforators were determined from operative reports. Chi-square and t-test or nonparametric Fisher's exact test and Wilcoxon two-sample test were used for discrete and continuous variable, respectively, as applicable. Logistic regression was used for multivariable analyses. RESULTS: Of 628 flaps, 305 were medial row (58.7%), 159 were lateral row (30.6%), and 55 had both rows (10.6%). Partial flap loss was higher in both rows (p = 0.003). Fat necrosis was higher with medial (p = 0.03) and both rows (p = 0.01) when compared with lateral using multivariable analysis. Hernia or bulge was higher in lateral row flaps (lateral: 8/157, 5.1%; medial, 5/299, 1.7%; both, 0/55; p = 0.05); however, mesh was more commonly used in both row flaps (p = 0.05). There was no difference in fat necrosis or abdominal morbidity between single and multiple perforators. CONCLUSION: There was no difference in fat necrosis based on the number or row of perforators. The lateral row provides adequate perfusion but may be associated with an elevated risk of hernia or bulge. Patients may benefit from mesh, especially when both rows are dissected.

Ascorbic Acid Reduces Neurotransmission, Synaptic Plasticity, and Spontaneous Hippocampal Rhythms in In Vitro Slices.

Ascorbic acid (AA; a.k.a. vitamin C) is well known for its cellular protection in environments of high oxidative stress. Even though physiological concentrations of AA in the brain are significant (0.2-10 mM), surprisingly little is known concerning the role of AA in synaptic neurotransmission under normal, non-disease state conditions. Here, we examined AA effects on neurotransmission, plasticity and spontaneous network activity (i.e., sharp waves and high frequency oscillations; SPW-HFOs), at the synapse between area 3 and 1 of the hippocampal cornu ammonis region (CA3 and CA1) using an extracellular multi-electrode array in in vitro mouse hippocampal slices. We found that AA decreased evoked field potentials (fEPSPs, IC50 = 0.64 mM) without affecting V50s or paired pulse facilitation indicating normal neurotransmitter release mechanisms. AA decreased presynaptic fiber volleys but did not change fiber volley-to-fEPSP coupling, suggesting reduced fEPSPs resulted from decreased fiber volleys. Inhibitory effects were also observed in CA1 stratum pyramidale where greater fEPSPs were required for population spikes in the presence of AA suggesting an impact on the intrinsic excitability of neurons. Other forms of synaptic plasticity and correlates of memory (i.e., short- and long-term potentiation) were also significantly reduced by AA as was the incidence of spontaneous SPW-HFOs. AA decreased SPW amplitude with a similar IC50 as fEPSPs (0.65 mM). Overall, these results indicate that under normal conditions AA significantly regulates neurotransmission, plasticity, and network activity by limiting excitability. Thus, AA may participate in refinement of signal processing and memory formation, as well as protecting against pathologic excitability.

Pharmacoresponsiveness of spontaneous recurrent seizures and the comorbid sleep disorder of epileptic Kcna1-null mice.

Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.

Ketogenic diet-mediated seizure reduction preserves CA1 cell numbers in epileptic Kcna1-null mice: An unbiased stereological assessment.

There is growing evidence for the disease-modifying potential of metabolic therapies, including the ketogenic diet (KD), which is used to treat medically intractable epilepsy. However, it remains unclear whether the KD exerts direct effects on histopathological changes in epileptic brain, or whether the changes are a consequence of diet-induced reduction in seizure activity. Here, we used unbiased stereological techniques to quantify the seizure-induced reduction in cell number in the CA1 region of the hippocampus of epileptic Kcna1-null mice and compared the effects of the KD with that of phenobarbital (PB), a widely employed anti-seizure drug. Our data suggest that the anti-seizure activity of the KD or PB was similar. However, CA1 cell numbers of KD-treated hippocampi were not significantly different from those seen in wild-type (WT) mice, whereas CA1 cell counts in standard diet and PB-treated Kcna1-null mice were 23% and 31% lower than WT animals, respectively. These results support the notion that structural protection of cells may involve more than seizure attenuation, and that the KD engages mechanisms that also promote or restore hippocampal morphological integrity.