Diet composition and sterilization modifies intestinal microbiome diversity and burden of Theiler's virus infection-induced acute seizures.

OBJECTIVE: Brain infection with Theiler's murine encephalomyelitis virus (TMEV) in C57BL/6J mice can induce acquired epileptogenesis. Diet alters acute seizure incidence in TMEV-infected mice; yet it is unclear whether intestinal dysbiosis may also impact acute or chronic behavioral comorbidities. This study thus assessed the impact of diet formulation and sterilization on acute seizure presentation, gut microbiome composition, and epilepsy-related chronic behavioral comorbidities. METHODS: Baseline fecal samples were collected from male C57BL/6J mice (4- to 5-weeks-old; Jackson Labs) upon facility arrival. Mice were randomized to either autoclaved (AC) or irradiated diet (IR) (Prolab RMH 3000) or IR (Picolab 5053). Three days later, mice underwent intracerebral TMEV or phosphate-buffered saline (PBS) injection. Fecal samples were collected from a subset of mice at infection (Day 0) and Day 7 post-infection. Epilepsy-related working memory deficits and seizure threshold were assessed 6 weeks post-infection. Gut microbiome diversity was determined by 16S rRNA amplicon sequencing of fecal samples. RESULTS: TMEV-infected mice displayed acute handling-induced seizures, regardless of diet: 28 of 57 IR Picolab 5053 (49.1%), 30 of 41 IR Prolab RMH 3000 (73.2%), and 47 of 77 AC Prolab RMH 3000 (61%) mice displayed seizures. The number of observed seizures differed significantly by diet: IR Picolab 5053 diet-fed mice had 2.2 ± 2.8 seizures (mean ± standard deviation), IR Prolab RMH 3000 diet-fed mice had 3.5 ± 2.9 seizures, and AC Prolab RMH 3000 diet-fed mice had 4.4 ± 3.8 seizures during the 7-day monitoring period. Gut microbiome composition differed significantly in TMEV-infected mice fed the AC Prolab RMH 3000 diet, with measured differences in gram-positive bacteria. These mice also displayed worsened long-term working memory deficits. SIGNIFICANCE: Diet-induced differences in intestinal dysbiosis in the TMEV model are associated with marked changes in acute seizure presentation, symptomatic recovery, and onset of chronic behavioral comorbidities of epilepsy. Our study reveals a novel disease-modifying impact of dietary manipulation on intestinal bacterial species after TMEV-induced acute seizures.

Continuous seizure emergency evoked in mice with pharmacological, electrographic, and pathological features distinct from status epilepticus.

OBJECTIVES: Benzodiazepines are the standard of care for the management of sustained seizure emergencies, including status epilepticus (SE) and seizure clusters. Seizure clusters are a variably defined seizure emergency wherein a patient has multiple seizures above a baseline rate, with intervening periods of recovery, distinguishing clusters from SE. Although these seizure emergencies are phenotypically distinct, the precise pathophysiological and mechanistic differences between SE and seizure clusters are understudied. Emergency-specific preclinical models may differentiate the behavioral and pathological mechanisms that are acutely associated with seizure emergencies and seizure termination to better manage these events. METHODS: Herein we characterize a novel model of sustained seizure emergency induced in CF-1 mice through the combined administration of high-dose phenytoin (PHT; 50 mg/kg, i.p.) and pentylenetetrazol (PTZ; 100 mg/kg, s.c.). RESULTS: We presently describe a mouse model of sustained seizure emergency that is pathologically, pharmacologically, and behaviorally distinct from SE. Acute administration of PHT 1 h prior to PTZ led to significantly more mice with unremitting continuous seizure activity (CSA; 73.4%) vs vehicle-pretreated mice (13.8%; p < .0001). CSA was sensitive to lorazepam and valproic acid when administered at seizure onset and 30 minutes later. Carbamazepine worsened seizure control and post-CSA survival. Mice in CSA exhibited electroencephalography (EEG) patterns distinct from kainic acid-induced SE and PTZ alone, clearly differentiating CSA from SE and PTZ-induced myoclonic seizures. Neuropathological assessment by Fluoro-Jade C staining of brains collected 24 h post-CSA revealed no neurodegeneration in any mouse that underwent CSA, whereas there was widespread neuronal death in brains from KA-SE mice. Finally, immunohistochemistry revealed acute seizure-induced astrogliosis (glial fibrillary acid protein; GFAP) in hippocampal structures, whereas hippocampal neuronal nuclei (NeuN) protein expression was only reduced in KA-SE mice. SIGNIFICANCE: We present a novel mouse model on which to further elucidate the mechanistic differences between sustained seizure emergencies (ie, SE and seizure clusters) to improve clinical interventions and define mechanisms of seizure termination.

Development of an antiepileptogenesis drug screening platform: Effects of everolimus and phenobarbital.

OBJECTIVE: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS. METHODS: Rats were administered either everolimus (2-3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5-7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden. RESULTS: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset. SIGNIFICANCE: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.

Alzheimer's Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation.

Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.

Loss of presenilin 2 age-dependently alters susceptibility to acute seizures and kindling acquisition.

Patients with Alzheimer's disease (AD) experience seizures at higher rates than the general population of that age, suggesting an underexplored role of hyperexcitability in AD. Genetic variants in presenilin (PSEN) 1 and 2 genes lead to autosomal dominant early-onset AD (ADAD); patients with PSEN gene variants also report seizures. Pharmacological control of seizures in AD may be disease-modifying. Preclinical efficacy of FDA-approved antiseizure drugs (ASDs) is well defined in young adult rodents; however, the efficacy of ASDs in aged rodents with chronic seizures is less clear. The mechanism by which ADAD genes lead to AD remains unclear, and even less studied is the pathogenesis of epilepsy in AD. PSEN variants generally all result in a biochemical loss of function (De Strooper, 2007). We herein determined whether well-established models of acute and chronic seizure could be used to explore the relationship between AD genes and seizures through investigating whether loss of normal PSEN2 function age-dependently influenced susceptibility to seizures and/or corneal kindling acquisition. PSEN2 knockout (KO) and age-matched wild-type (WT) mice were screened from 2- to 10-months-old to establish age-dependent focal seizure threshold. Additionally, PSEN2 KO and WT mice aged 2- and 8-months-old underwent corneal kindling such that mice were aged 3- and 9-months old at the beginning of ASD efficacy testing. We then defined the dose-dependent efficacy of mechanistically distinct ASDs on kindled seizures of young versus aged mice to better understand the applicability of corneal kindling to real-world use for geriatric patients. PSEN2 KO mice demonstrated early-life reductions in seizure threshold. However, kindling acquisition was delayed in 2-month-old PSEN2 KO versus WT mice. Young male WT mice took 24.3 ± 1.3 (S.E.M.) stimulations to achieve kindling criterion, whereas age-matched PSEN2 KO male mice took 41.2 ± 1.1 stimulations (p < .0001). The rate of kindling acquisition of 8-month-old mice was no longer different from WT. This study demonstrates that loss of normal PSEN2 function is associated with age-dependent changes in the in vivo susceptibility to acute seizures and kindling. Loss of normal PSEN2 function may be an underexplored molecular contributor to seizures. The use of validated models of chronic seizures in aged rodents may uncover age-related changes in susceptibility to epileptogenesis and/or ASD efficacy in mice with AD-associated genotypes, which may benefit the management of seizures in AD.

Antiseizure drug efficacy and tolerability in established and novel drug discovery seizure models in outbred vs inbred mice.

OBJECTIVE: Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well-established mouse acute and chronic seizure models: for example, maximal electroshock (MES), 6 Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) vs investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility. However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl/6 vs outbred CF-1 mice, both of which are often used for ASD discovery. METHODS: We defined the strain-related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6 Hz, and corneal-kindled mouse). We further quantified the strain-related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Finally, we describe a novel pharmacoresistant corneal-kindling protocol that is suitable for moderate-throughput ASD screening and demonstrates highly differentiated ASD sensitivity. RESULTS: We report significant strain-related differences in the MES ED50 of valproic acid (CF-1 ED50: 90 mg/kg [95% confidence interval (CI) 165-214] vs C57Bl/6: 276 mg/kg [226-366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6 Hz test (CF-1: 22.5 mg/kg [14.7-30.2] vs C57Bl/6: >500 mg/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Furthermore, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF-1, but not C57Bl/6, mice. SIGNIFICANCE: Altogether, this study provides strain-related information to differentiate investigational agents from ASD standards-of-care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug-resistant epilepsy.

Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype.

Methylcellulose (MC; 0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. When administered by the oral (PO) route, MC is considered a Food and Drug Administration "generally recognized as safe" compound. Yet, there is limited data pertaining to the tolerability and impact on model fidelity of repeated intraperitoneal administration of 0.5% MC. Chronic administration of high-concentration MC (2%-2.5%) has been used to induce anemia, splenomegaly, and lesions in multiple organ systems in several preclinical species. Histopathological findings from a diagnostic pathologic analysis of a single mouse from our laboratory with experimentally induced chronic seizures that had received repeated intraperitoneal administration of antiseizure drugs delivered in MC revealed similar widespread lesions. This study thus tested the hypothesis that chronic administration of intraperitoneal, but not PO, MC incites histologic lesions without effects on preclinical phenotype. Male CF-1 mice (n = 2-14/group) were randomized to receive either 6 weeks of twice weekly 0.5% MC or saline (intraperitoneal or PO) following induction of chronic seizures. Histology of a subset of mice revealed lesions in kidney, liver, mediastinal lymph nodes, mesentery, aorta, and choroid plexus only in intraperitoneal MC-treated mice (n = 7/7). Kindled mice that received MC PO (n = 5) or saline (intraperitoneal n = 6, PO n = 3) had no lesions. There were no effects of intraperitoneal MC treatment on body weight, appearance, seizure stability, or behavior. Nonetheless, our findings suggest that repeated intraperitoneal, but not PO, MC elicits systemic organ damage without impacting the model phenotype, which may confound interpretation of investigational drug-induced histologic lesions. SIGNIFICANCE STATEMENT: Methylcellulose (0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. Herein, we demonstrate that repeated administration of 0.5% methylcellulose by the intraperitoneal, but not oral, route results in systemic inflammation and presence of foam-laden macrophages but does not impact the behavioral phenotype of a rodent model of neurological disease.

Lamotrigine-resistant corneal-kindled mice: A model of pharmacoresistant partial epilepsy for moderate-throughput drug discovery.

OBJECTIVE: Despite numerous treatments for epilepsy, over 30% of patients remain resistant to available antiseizure drugs (ASDs). Thus, there is a strong need for more effective ASDs for these individuals. Early ASD discovery has historically relied on acute in vivo seizure models (maximal electroshock, subcutaneous pentylenetetrazol, 6 Hz), which lack the pathophysiology that defines chronic epilepsy. Etiologically relevant rodent models of pharmacoresistant epilepsy exist (eg, phenytoin (PHT)- and lamotrigine (LTG)-resistant amygdala-kindled rat and focal kainic acid mouse), but these models are resource- and labor-intensive and thus unsuitable for frontline ASD discovery. METHODS: We adapted the LTG-resistant amygdala-kindled rat protocol to the 60 Hz corneal-kindled mouse (CKM) to develop a medium-throughput model of pharmacoresistant chronic seizures. Male CF-1 mice were administered either vehicle (VEH; 0.5% methylcellulose) or LTG (8.5 mg/kg, ip) 30 minutes prior to each twice-daily corneal stimulation until mice achieved kindling criterion. Prototype ASDs were then evaluated in fully kindled mice. Compounds with specific mechanisms of action of interest to epilepsy (fluoxetine, minocycline, and celecoxib) were also evaluated. RESULTS: LTG did not modify kindling acquisition. A challenge dose of 17 mg/kg (ip) LTG did not block the secondarily generalized kindled seizure in LTG-kindled mice (mean seizure score [MSS] ± standard error of the mean: 5.67 ± 0.14), whereas VEH-treated mice were sensitive (MSS: 2.25 ± 0.30); confirming LTG-resistance. LTG-resistant CKM were also resistant to carbamazepine, retigabine, and valproic acid at doses that significantly reduced MSS in VEH-treated kindled mice. Fluoxetine, minocycline, and celecoxib were ineffective at the doses tested in either kindled cohort. Finally, the behavioral phenotype of LTG-resistant CKM was also characterized. CKM demonstrated exacerbated hyperexcitability and increased anxiety-like behavior in an open field relative to sham-kindled mice regardless of LTG sensitivity. SIGNIFICANCE: The pharmacoresistant LTG-resistant CKM provides an etiologically relevant moderate-throughput platform that is suitable for early compound discovery before advancing to more resource-intensive models of epilepsy.

Paraumbilical perforator flap for soft tissue reconstruction of the forearm.

Numerous flaps exist for coverage of injuries to the upper extremity, ranging from local, to regional, to free tissue transfer. The choice of flap is dependent on a variety of factors, including patient, functional needs, and depth of injury. The paraumbilical perforator (PUP) flap for upper extremity coverage can offer the benefits and versatility of pedicled and free flaps while avoiding some of the donor-site morbidity and risks of free tissue transfer. We report the indications and management of two clinical cases that exemplify PUP flap application. Technical points of flap harvest, inset, timing of pedicle division, and pertinent anatomy are discussed.

Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset of Alzheimer's disease-related neuropathology.

OBJECTIVE: Hyperexcitability is intimately linked to Alzheimer's disease (AD) pathology, but the precise timing and contributions of neuronal hyperexcitability to disease progression is unclear. Seizure induction in rodent AD models can uncover new therapeutic targets. Further, investigator-evoked seizures can directly establish how hyperexcitability and AD-associated risk factors influence neuropathological hallmarks and disease course at presymptomatic stages. METHODS: Corneal kindling is a well-characterized preclinical epilepsy model that allows for precise control of seizure history to pair to subsequent behavioral assessments. 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control male and female mice were thus sham or corneal kindled for 2 weeks. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid ß levels in hippocampus and prefrontal cortex were quantified. RESULTS: APP/PS1 females were more susceptible to corneal kindling. However, regardless of sex, APP/PS1 mice experienced extensive seizure-induced mortality versus kindled Tg- controls. PSEN2-N141I mice were not negatively affected by corneal kindling. Mortality correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression versus controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice also exhibited soluble amyloid ß upregulation and glial reactivity without plaque deposition. SIGNIFICANCE: Evoked convulsive seizures and neuronal hyperexcitability in pre-symptomatic APP/PS1 mice promoted premature mortality without pathological Aß plaque deposition, whereas PSEN2-N141I mice were unaffected. Disruptions in serotonin pathway metabolism in APP/PS1 mice was associated with increased glial reactivity without Aß plaque deposition, demonstrating that neuronal hyperexcitability in early AD causes pathological Aß overexpression and worsens long-term outcomes through a serotonin-related mechanism.

Chronic seizures induce sex-specific cognitive deficits with loss of presenilin 2 function.

Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.

Chronic evoked seizures in young pre-symptomatic APP/PS1 mice induce serotonin changes and accelerate onset on Alzheimer's disease-related neurpathology.

OBJECTIVE: People with early-onset Alzheimer's disease (AD) are at elevated seizure risk. Further, chronic seizures in pre-symptomatic stages may disrupt serotonin pathway-related protein expression, precipitating the onset of AD-related pathology and burden of neuropsychiatric comorbidities. METHODS: 2-3-month-old APP/PS1, PSEN2-N141I, and transgenic control mice were sham or corneal kindled for 2 weeks to model chronic seizures. Seizure-induced changes in glia, serotonin pathway proteins, and amyloid beta; levels in hippocampus and prefrontal cortex were quantified. RESULTS: APP/PS1 mice experienced worsened mortality versus kindled Tg- controls. APP/PS1 females were also more susceptible to chronic kindled seizures. These changes correlated with a marked downregulation of hippocampal tryptophan hydroxylase 2 and monoamine oxidase A protein expression compared to controls; these changes were not detected in PSEN2-N141I mice. Kindled APP/PS1 mice exhibited amyloid beta; overexpression and glial overactivity without plaque deposition. PSEN2 protein expression was AD model-dependent. SIGNIFICANCE: Seizures evoked in pre-symptomatic APP/PS1 mice promotes premature mortality in the absence of pathological amyloid deposition. Disruptions in serotonin pathway metabolism are associated with increased glial reactivity and PSEN2 downregulation without amyloid beta; deposition. This study provides the first direct evidence that seizures occurring prior to amyloid beta, plaque accumulation worsen disease burden in an AD genotype-specific manner.

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy.

Older people represent the fastest growing group with epilepsy diagnosis. For example, cerebrovascular disease may underlie roughly 30-50% of epilepsy in older adults and seizures are also an underrecognized comorbidity of Alzheimer's disease (AD). As a result, up to 10% of nursing home residents may take antiseizure medicines (ASMs). Despite the greater incidence of epilepsy in older individuals and increased risk of comorbid seizures in people with AD, aged animals with seizures are strikingly underrepresented in epilepsy drug discovery practice. Increased integration of aged animals into preclinical epilepsy drug discovery could better inform the potential tolerability and pharmacokinetic interactions in aged individuals as the global population becomes increasingly older. Quite simply, the ASMs on the market today were brought forth based on efficacy in young adult, neurologically intact rodents; preclinical information concerning the efficacy and safety of promising ASMs is not routinely evaluated in aged animals. Integrating aged animals more often into basic epilepsy research may also uncover novel treatments for hyperexcitability. For example, cannabidiol and fenfluramine demonstrated clear efficacy in syndrome-specific pediatric models that led to a paradigm shift in the perceived value of pediatric models for ASM discovery practice; aged rodents with seizures or rodents with aging-related neuropathology represent an untapped resource that could similarly change epilepsy drug discovery. This review, therefore, summarizes how aged rodent models have thus far been used for epilepsy research, what studies have been conducted to assess ASM efficacy in aged rodent seizure and epilepsy models, and lastly to identify remaining gaps to engage aging-related neurological disease models for ASM discovery, which may simultaneously reveal novel mechanisms associated with epilepsy.

Diurnal burden of spontaneous seizures in early epileptogenesis in the post-kainic acid rat model of epilepsy.

Patients with epilepsy can experience diurnal seizure patterns. However, few studies in rodent models of temporal lobe epilepsy (TLE) routinely quantify the diurnal pattern of spontaneous recurrent seizures (SRS), and those that have conducted such assessments used small groups. This study thus aimed to define whether there was a diurnal pattern of SRS in the early phases of epileptogenesis in a large cohort (n = 40) of post-kainic acid (KA)-induced status epilepticus (SE) male Sprague Dawley rats. Rats were monitored by continuous 24/7 video-EEG in two-week epochs up to 6 weeks post-KA-induced SE. The total number of SRS by 6 weeks post-SE correlated to body weight at the time of SE insult (R2  = .1465, P = .0143). The total number of spontaneous behavioral and electrographic seizures, seizure severity, and seizure burden was recorded during lights ON (light) or lights OFF (dark) phases. All measures significantly increased with time post-SE; we detected significantly more seizures during the lights OFF phase of the post-SE monitoring periods. Moreover, a subset of rats demonstrated marked seizure preference in the lights OFF phase. Our study confirms that a diurnal pattern of SRS is variably detectable in early epileptogenesis in this model of TLE.

Solutions to challenging digital replantations.

Replantation of amputated digits remains one of the most challenging areas in plastic and reconstructive surgery. Complicated cases of digital amputation, such as fingertip amputations, multidigital amputations, and so forth, pose an even greater challenge, requiring extraordinary solutions for successful replantation. The authors present their experience with complicated digital replantations at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School. Cases presented include fingertip replantation, replantation of a finger with impairment of arterial inflow, and two cases of multidigital amputations. In one case of multidigital amputation, heterodigital replantation was performed, and in the other case, a minute skin neurovascular free flap from a nonreplantable finger was used for the reconstruction of another injured finger. Presented cases demonstrate various tools that can be successfully used in the performance of challenging digital replantations.

Comparison of wound irrigation and tangential hydrodissection in bacterial clearance of contaminated wounds: results of a randomized, controlled clinical study.

Thorough irrigation of contaminated or infected traumatic and open surgical wounds is considered standard practice. High-power pulse lavage is frequently used to facilitate the removal of surface contaminants and bacteria but studies to compare the results of various irrigation techniques are limited. The purpose of this randomized, controlled clinical study was to compare the ability of a high-pressure parallel waterjet (pressure range 5,025 to 7,360 psi) to pulse lavage (pressure 40 psi) in reducing wound bacterial counts. The higher velocity instrument utilizes a waterjet oriented parallel to the surface of the wound and can be used to cut and remove necrotic tissues. After obtaining informed consent, 21 patients who presented with open surgical and traumatic wounds were randomly assigned to high-pressure parallel waterjet (n = 12) or pulse lavage (n = 9). Pre- and post irrigation tissue culture results showed an average decrease in absolute bacterial counts of 90.8% in the high-pressure parallel waterjet and 86.9% in the pulse lavage group. The difference between the two treatment groups was not statistically significant. The results of this study confirm that cleansing contaminated or infected acute wounds using high pressure (at least 15 psi) reduces wound bacterial counts. Studies to compare the clinical outcomes of various irrigation techniques and pressure ranges are warranted and the potential benefit of selective debridement using the high-pressure parallel waterjet should be investigated.

Complex modeling: a strategy and software program for combining multiple information sources to solve ill posed structure and nanostructure inverse problems.

A strategy is described for regularizing ill posed structure and nanostructure scattering inverse problems (i.e. structure solution) from complex material structures. This paper describes both the philosophy and strategy of the approach, and a software implementation, DiffPy Complex Modeling Infrastructure (DiffPy-CMI).

Infection with nontuberculous mycobacterium after injection of adulterated silicone fluid.

A 57-year-old woman presented with a predominantly right-sided cellulitic area of her buttock after receiving multiple bilateral silicone injections in the buttocks. The workup revealed subcutaneous infection with rapidly growing mycobacteria. Surgical management and etiologic factors are discussed, and a review of the literature is presented.

Corrugation in exfoliated graphene: an electron microscopy and diffraction study.

Low-energy electron microscopy and microprobe diffraction are used to image and characterize corrugation in SiO(2)-supported and suspended exfoliated graphene at nanometer length scales. Diffraction line-shape analysis reveals quantitative differences in surface roughness on length scales below 20 nm which depend on film thickness and interaction with the substrate. Corrugation decreases with increasing film thickness, reflecting the increased stiffness of multilayer films. Specifically, single-layer graphene shows a markedly larger short-range roughness than multilayer graphene. Due to the absence of interactions with the substrate, suspended graphene displays a smoother morphology and texture than supported graphene. A specific feature of suspended single-layer films is the dependence of corrugation on both adsorbate load and temperature, which is manifested by variations in the diffraction line shape. The effects of both intrinsic and extrinsic corrugation factors are discussed.

Surgical wound bed preparation of chronic and acute wounds.

Our aging population has presented us with many new challenges. One such challenge is the need to manage an increase in wound-related problems effectively and efficiently. Over time, two parallel, yet divergent, management systems have developed. One strategy, used by medical specialists, uses a variety of dressings, topical enzymes, and local and systemic medications ultimately aimed at the promotion of healing by secondary intention or, in some cases, optimization of the wound for surgical reconstruction. In the second strategy, used by surgeons, early surgical intervention is used to prepare the wound for reconstruction in a timelier manner while promoting the healing process. This article reviews the development of these two distinct management systems and their areas of commonality and sets forth a new model to support the role of surgery in the treatment of problematic wounds.