Polyamine Modulation of Anticonvulsant Drug Response: A Potential Mechanism Contributing to Pharmacoresistance in Chronic Epilepsy

Despite the development of numerous novel anticonvulsant drugs, ~30% of epilepsy patients remain refractory to antiepileptic drugs (AEDs). Many established and novel AEDs reduce hyperexcitability via voltage- and use-dependent inhibition of voltage-gated Na⁺ channels. For the widely used anticonvulsant carbamazepine (CBZ), use-dependent block of Na⁺ channels is significantly reduced both in experimental and human epilepsy. However, the molecular underpinnings of this potential cellular mechanism for pharmacoresistance have remained enigmatic.

Here, we describe the mechanism that leads to the emergence of CBZ-resistant Na⁺ channels. We focused on the endogenous polyamine system, which powerfully modulates Na⁺ channels in a use-dependent manner. We had shown previously that the intracellular polyamine spermine is reduced in chronic epilepsy, resulting in increased persistent Na⁺ currents. Because spermine and CBZ both bind use-dependently in spatial proximity within the Na⁺ channel pore, we hypothesized that spermine loss might also be related to diminished CBZ response. Using the pilocarpine model of refractory epilepsy in male rats and whole-cell patch-clamp recordings, we first replicated the reduction of use-dependent block by CBZ in chronically epileptic animals. We then substituted intracellular spermine via the patch pipette in different concentrations. Under these conditions, we found that exogenous spermine significantly rescues use-dependent block of Na⁺ channels by CBZ. These findings indicate that an unexpected modulatory mechanism, depletion of intracellular polyamines, leads both to increased persistent Na⁺ currents and to diminished CBZ sensitivity of Na⁺ channels. These findings could lead to novel strategies for overcoming pharmacoresistant epilepsy that target the polyamine system.

SIGNIFICANCE STATEMENT Pharmacoresistant epilepsy affects ~18 million people worldwide, and intense efforts have therefore been undertaken to uncover the underlying molecular and cellular mechanisms. One of the key known candidate mechanisms of pharmacoresistance has been a loss of use-dependent Na⁺ channel block by the anticonvulsant carbamazepine (CBZ), both in human and experimental epilepsies. Despite intense scrutiny, the molecular mechanisms underlying this phenomenon have not been elucidated. We now show that a loss of intracellular spermine in chronic epilepsy is a major causative factor leading to the development of CBZ-resistant Na⁺ currents. This finding can be exploited both for the screening of anticonvulsants in expression systems, and for novel strategies to overcome pharmacoresistance that target the polyamine system.

Neural Signatures of the Processing of Temporal Patterns in Sound

The ability to detect regularities in sound (i.e., recurring structure) is critical for effective perception, enabling, for example, change detection and prediction. Two seemingly unconnected lines of research concern the neural operations involved in processing regularities: one investigates how neural activity synchronizes with temporal regularities (e.g., frequency modulation; FM) in sounds, whereas the other focuses on increases in sustained activity during stimulation with repeating tone-frequency patterns. In three electroencephalography studies with male and female human participants, we investigated whether neural synchronization and sustained neural activity are dissociable, or whether they are functionally interdependent. Experiment I demonstrated that neural activity synchronizes with temporal regularity (FM) in sounds, and that sustained activity increases concomitantly. In Experiment II, phase coherence of FM in sounds was parametrically varied. Although neural synchronization was more sensitive to changes in FM coherence, such changes led to a systematic modulation of both neural synchronization and sustained activity, with magnitude increasing as coherence increased. In Experiment III, participants either performed a duration categorization task on the sounds, or a visual object tracking task to distract attention. Neural synchronization was observed regardless of task, whereas the sustained response was observed only when attention was on the auditory task, not under (visual) distraction. The results suggest that neural synchronization and sustained activity levels are functionally linked: both are sensitive to regularities in sounds. However, neural synchronization might reflect a more sensory-driven response to regularity, compared with sustained activity which may be influenced by attentional, contextual, or other experiential factors.

SIGNIFICANCE STATEMENT Optimal perception requires that the auditory system detects regularities in sounds. Synchronized neural activity and increases in sustained neural activity both appear to index the detection of a regularity, but the functional interrelation of these two neural signatures is unknown. In three electroencephalography experiments, we measured both signatures concomitantly while listeners were presented with sounds containing frequency modulations that differed in their regularity. We observed that both neural signatures are sensitive to temporal regularity in sounds, although they functionally decouple when a listener is distracted by a demanding visual task. Our data suggest that neural synchronization reflects a more automatic response to regularity compared with sustained activity, which may be influenced by attentional, contextual, or other experiential factors.

This Week in The Journal

miR126-5p Downregulation Facilitates Axon Degeneration and NMJ Disruption via a Non-Cell-Autonomous Mechanism in ALS

Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non–cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non–cell-autonomous mechanism of motor neuron degeneration in ALS.

SIGNIFICANCE STATEMENT Despite some progress, currently no effective treatment is available for amyotrophic lateral sclerosis (ALS). We suggest a novel regulatory role for miR126-5p in ALS and demonstrate, for the first time, a mechanism by which alterations in miR126-5p contribute to axon degeneration and NMJ disruption observed in ALS. We show that miR126-5p is altered in ALS models and that it can modulate Sema3 and NRP protein expression. Furthermore, NRP1 elevations in motor neurons and muscle secretion of Sema3A contribute to axon degeneration and NMJ disruption in ALS. Finally, overexpressing miR126-5p is sufficient to transiently rescue NMJ disruption and axon degeneration both in vitro and in vivo.

A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration

Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca²⁺ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCC during brain development remain unclear. Calcium signaling has been shown to be essential for neurodevelopmental processes such as sculpting of neurites, functional wiring, and fine tuning of growing networks. To investigate this relationship, we performed submembraneous calcium imaging using a membrane-tethered genetically encoded calcium indicator (GECI) Lck-G-CaMP7. We successfully recorded spontaneous regenerative calcium transients (SRCaTs) in developing mouse excitatory cortical neurons prepared from both sexes before synapse formation. SRCaTs originated locally in immature neurites independently of somatic calcium rises and were significantly more elevated in the axons than in dendrites. SRCaTs were not blocked by tetrodoxin, a Na⁺ channel blocker, but were strongly inhibited by hyperpolarization, suggesting a voltage-dependent source. Pharmacological and genetic manipulations revealed the critical importance of the Ca_v1.2 (CACNA1C) pore-forming subunit of L-type VGCCs, which were indeed expressed in immature mouse brains. Consistently, knocking out Ca_v1.2 resulted in significant alterations of neurite outgrowth. Furthermore, expression of a gain-of-function Ca_v1.2 mutant found in Timothy syndrome, an autosomal dominant multisystem disorder exhibiting syndromic autism, resulted in impaired radial migration of layer 2/3 excitatory neurons, whereas postnatal abrogation of Ca_v1.2 enhancement could rescue cortical malformation. Together, these lines of evidence suggest a critical role for spontaneous opening of L-type VGCCs in neural development and corticogenesis and indicate that L-type VGCCs might constitute a perinatal therapeutic target for neuropsychiatric calciochannelopathies.

SIGNIFICANCE STATEMENT Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca²⁺ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCCs during brain development remain unclear. We here combined the latest Ca²⁺ indicator technology, quantitative pharmacology, and in utero electroporation and found a hitherto unsuspected role for L-type VGCCs in determining the Ca²⁺ signaling landscape of mouse immature neurons. We found that malfunctional L-type VGCCs in immature neurons before birth might cause errors in neuritic growth and cortical migration. Interestingly, the retarded corticogenesis phenotype was rescued by postnatal correction of L-type VGCC signal aberration. These findings suggest that L-type VGCCs might constitute a perinatal therapeutic target for neurodevelopment-associated psychiatric disorders.

The Frequency Response of Outer Hair Cell Voltage-Dependent Motility Is Limited by Kinetics of Prestin

The voltage-dependent protein SLC26a5 (prestin) underlies outer hair cell electromotility (eM), which is responsible for cochlear amplification in mammals. The electrical signature of eM is a bell-shaped nonlinear capacitance (NLC), deriving from prestin sensor-charge (Q_p) movements, which peaks at the membrane voltage, V_h, where charge is distributed equally on either side of the membrane. Voltage dependencies of NLC and eM differ depending on interrogation frequency and intracellular chloride, revealing slow intermediate conformational transitions between anion binding and voltage-driven Q_p movements. Consequently, NLC exhibits low-pass characteristics, substantially below prevailing estimates of eM frequency response. Here we study in guinea pig and mouse of either sex synchronous prestin electrical (NLC, Q_p) and mechanical (eM) activity across frequencies under voltage clamp (whole cell and microchamber). We find that eM and Q_p magnitude and phase correspond, indicating tight piezoelectric coupling. Electromechanical measures (both NLC and eM) show dual-Lorentzian, low-pass behavior, with a limiting (₂) time constant at V_h of 32.6 and 24.8 μs, respectively. As expected for voltage-dependent kinetics, voltage excitation away from V_h has a faster, flatter frequency response, with our fastest measured ₂ for eM of 18.2 μs. Previous observations of ultrafast eM ( 2 μs) were obtained at offsets far removed from V_h. We hypothesize that trade-offs in eM gain-bandwith arising from voltage excitation at membrane potentials offset from V_h influence the effectiveness of cochlear amplification across frequencies.

SIGNIFICANCE STATEMENT Of two types of hair cells within the organ of Corti, inner hair cells and outer hair cells, the latter evolved to boost sensitivity to sounds. Damage results in hearing loss of 40–60 dB, revealing amplification gains of 100–1000x that arise from voltage-dependent mechanical responses [electromotility (eM)]. eM, driven by the membrane protein prestin, may work beyond 70 kHz. However, this speed exceeds, by over an order of magnitude, kinetics of typical voltage-dependent membrane proteins. We find eM is actually low pass in nature, indicating that prestin bears kinetics typical of other membrane proteins. These observations highlight potential difficulties in providing sufficient amplification beyond a cutoff frequency near 20 kHz. Nevertheless, observed trade-offs in eM gain-bandwith may sustain cochlear amplification across frequency.

Prostaglandin Transporter OATP2A1/SLCO2A1 Is Essential for Body Temperature Regulation during Fever

Prostaglandin E₂ (PGE₂) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of Slco2a1 deficiency on the body core temperature (Tc) and on the PGE₂ concentration in hypothalamus interstitial fluid (C_isf) and CSF (C_csf) of lipopolysaccharide (LPS; 100 μg/kg, i.p.)-treated mice of both sexes. Slco2a1^–/– mice did not develop a febrile response. C_csf was increased in Slco2a1^+/+ and Slco2a1^–/– mice, and C_csf of Slco2a1^–/– mice was well maintained at 5 h after LPS injection (1160 pg/ml) compared with Slco2a1^+/+ mice (316 pg/ml). A microdialysis study revealed that C_isf peaked at 2 h after LPS injection in Slco2a1^+/+ mice (841 pg/ml), whereas the increase in C_isf was negligible in Slco2a1^–/– mice. The PGE₂ plasma concentration in Slco2a1^–/– mice (201 pg/ml) was significantly higher than that in Slco2a1^+/+ mice (54 pg/ml) at 1 h after LPS injection, whereas the two groups showed similar PGE₂ concentrations in the hypothalamus. Strong Oatp2a1 immunoreactivity was observed in F4/80-positive microglia and perivascular cells and in brain capillary endothelial cells. The changes in Tc and C_isf seen in LPS-injected Slco2a1^+/+ mice were partially attenuated in monocyte-/macrophage-specific Slco2a1^–/– (Slco2a1^Fl/Fl/LysM^Cre/+) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of C_isf, possibly by regulating PGE₂ secretion from F4/80-positive glial cells and/or facilitating PGE₂ transport across the blood–brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation.

SIGNIFICANCE STATEMENT Fever is a physiological response caused by pyrogen-induced release of prostaglandin E₂ (PGE₂) in the hypothalamus, which plays a central role in regulating the set-point of body temperature. However, it is unclear whether the prostaglandin transporter OATP2A1/SLCO2A1 is involved in this response. We show here that LPS-induced fever is associated with increased PGE₂ concentration in hypothalamus interstitial fluid (C_isf), but not in CSF (C_csf), by means of a microdialysis study in global Slco2a1-knock-out mice and monocyte-/macrophage-specific Slco2a1-knock-out mice. The results suggest that OATP2A1 serves as a regulator of C_isf in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells and, therefore, may also play a role in PGE₂ transport across the blood–brain barrier.

Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ~2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (~7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ~2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs.

SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI tract [called interstitial cells of Cajal (ICCs)] that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI tract remains unknown. We developed a high-resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI tract.

Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6

The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system.

SIGNIFICANCE STATEMENT p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.

Suppression of AMPA Receptor Exocytosis Contributes to Hippocampal LTD

The decrease in number of AMPA-type glutamate receptor (AMPAR) at excitatory synapses causes LTD, a cellular basis of learning and memory. The number of postsynaptic AMPARs is regulated by the balance of exocytosis and endocytosis, and enhanced endocytosis of AMPAR has been suggested to underlie the LTD expression. However, it remains unclear how endocytosis and exocytosis of AMPAR change during LTD. In this study, we addressed this question by analyzing exocytosis and endocytosis of AMPAR by imaging super-ecliptic pHlorin (SEP)-tagged AMPAR around postsynaptic structure formed directly on the glass surface in the hippocampal culture prepared from rat embryos of both sexes. Contrary to a prevailing view on the LTD expression by endocytosis enhancement, the LTD induction by NMDA application only transiently enhanced endocytosis of SEP-tagged GluA1 subunits of AMPAR, which was counteracted by simultaneous augmentation of exocytosis. As a result, soon after the start of the LTD induction (~1 min), the surface AMPAR did not markedly decrease. Thereafter, the surface GluA1-SEP gradually decreased (2–5 min) and kept at a low level until the end of observation (>30 min). Surprisingly, this gradual and sustained decrease of surface AMPAR was accompanied not by the enhanced endocytic events of GluA1, but by the suppression of exocytosis. Together, our data highlight an unprecedented mechanism for the LTD expression by attenuation of exocytosis of AMPAR, but not by enhanced endocytosis, together with a reduction of postsynaptic AMPAR scaffolding protein PSD95.

SIGNIFICANCE STATEMENT It has been generally assumed that LTD is expressed by enhancement of AMPAR endocytosis. Previous studies reported that endocytosis-related protein was involved in LTD and that significant amount of cell-surface AMPAR moved into intracellular compartments during LTD. Here, we report changes of cell-surface amount of AMPAR, and where and when individual exocytosis and endocytosis occurred during LTD. Cell-surface AMPAR gradually decreased in synchrony with suppression of exocytosis but not with enhancement of endocytosis. These results suggest that the decrease of cell-surface AMPAR amount during LTD was caused not by enhancement of endocytosis but rather by suppression of exocytosis, which revises current understanding of the expression mechanism of LTD.

Expectations Do Not Alter Early Sensory Processing during Perceptual Decision-Making

Two factors play important roles in shaping perception: the allocation of selective attention to behaviorally relevant sensory features, and prior expectations about regularities in the environment. Signal detection theory proposes distinct roles of attention and expectation on decision-making such that attention modulates early sensory processing, whereas expectation influences the selection and execution of motor responses. Challenging this classic framework, recent studies suggest that expectations about sensory regularities enhance the encoding and accumulation of sensory evidence during decision-making. However, it is possible, that these findings reflect well documented attentional modulations in visual cortex. Here, we tested this framework in a group of male and female human participants by examining how expectations about stimulus features (orientation and color) and expectations about motor responses impacted electroencephalography (EEG) markers of early sensory processing and the accumulation of sensory evidence during decision-making (the early visual negative potential and the centro-parietal positive potential, respectively). We first demonstrate that these markers are sensitive to changes in the amount of sensory evidence in the display. Then we show, counter to recent findings, that neither marker is modulated by either feature or motor expectations, despite a robust effect of expectations on behavior. Instead, violating expectations about likely sensory features and motor responses impacts posterior alpha and frontal theta oscillations, signals thought to index overall processing time and cognitive conflict. These findings are inconsistent with recent theoretical accounts and suggest instead that expectations primarily influence decisions by modulating post-perceptual stages of information processing.

SIGNIFICANCE STATEMENT Expectations about likely features or motor responses play an important role in shaping behavior. Classic theoretical frameworks posit that expectations modulate decision-making by biasing late stages of decision-making including the selection and execution of motor responses. In contrast, recent accounts suggest that expectations also modulate decisions by improving the quality of early sensory processing. However, these effects could instead reflect the influence of selective attention. Here we examine the effect of expectations about sensory features and motor responses on a set of electroencephalography (EEG) markers that index early sensory processing and later post-perceptual processing. Counter to recent empirical results, expectations have little effect on early sensory processing but instead modulate EEG markers of time-on-task and cognitive conflict.

Problematic End Points in a Keratinocyte Carcinoma Chemoprevention Trial—Reply

In Reply We appreciate the close scrutiny of our published work and the opportunity to elaborate on the end points we used for analysis of the trial data. The VAKCC Trial primary end point was the rate of occurrence of keratinocyte carcinoma (KC) over the course of the 4-year trial. In the process of creating and executing this trial, however, the study team explicitly discussed that there were other important outcomes. In particular, while we did not have evidence to guide our estimation of the timing and duration of the effect of our intervention, if any, on the occurrence of KC, basal cell carcinoma, or squamous cell carcinoma (SCC), we realized that a short-term effect on risk (eg, during the first year) could be of considerable clinical importance even if the effect did not persist for the entire duration of the trial. We further recognized that even if there was a substantial effect in the first year, it could be lost in the 4-year results unless specifically examined. Hence, when analysis plans were discussed prior to unblinding the data, it was explicitly stated by the study chair, and summarized in the form of email guidance to the study statistician, that outcomes at 1 year were important to calculate and report. With the focus on completing the report, we chose not to officially amend the statistical analysis plan. This was an administrative decision that did not prevent appropriate analysis and should not prevent appropriate scientific interpretation. The final analyses, as reported, revealed a clinically and statistically significant 75% reduction in SCC risk in the first year. It is appropriate for this finding to influence the clinical care of those at high risk of face and ear SCC.

An Elderly Woman With Painful Buttock and Vulvar Ulcers

A woman in her 80s presented with somnolence, fatigue, lower urinary tract symptoms, and progressively worsening vulvar and buttock pain. What is your diagnosis?

Association of RARβ Expression With Lichen Sclerosus–Associated Vulvar Squamous Cell Carcinoma

This case-control study examines the association of retinoic acid receptor β tumor-suppressor gene with the onset and progression of lichen sclerosus–associated vulvar squamous cell carcinoma.

Problematic End Points in a Keratinocyte Carcinoma Chemoprevention Trial

To the Editor Treatment with topical fluorouracil, 5%, compared with placebo reduced risk of surgically treated squamous cell carcinoma (SCC) and Mohs surgery for keratinocyte carcinoma (KC) for 1 year, according to a randomized clinical trial (RCT) report. However, because neither of these outcomes was prespecified, these findings should be interpreted very cautiously and should not sway clinical practice.

Efficacy and Safety of Ozenoxacin for Treatment of Patients With Impetigo

This randomized clinical trial evaluates the efficacy, safety, and tolerability of ozenoxacin cream vs placebo in children and adults with impetigo.

Contributions by MC1R Variants to Melanoma Risk in Males and Females

This case-control study evaluates the association of melanocortin-1-receptor (MC1R) with melanoma risk in males vs females, adjusting for risk factors such as age, pigmentation, phenotype, signs of skin damage, and sun exposure.

An Evaluation of the Relationship among Urine, Air, and Hand Measures of Exposure to Bisphenol A (BPA) in US Manufacturing Workers

Abstract

Background

Exposure to bisphenol A (BPA) can be assessed using external and internal exposure measures. We examined the relationship between two measures of external BPA exposure (air and hand-wipe samples) and one of internal exposure (total BPA in urine) for a group of US manufacturing workers.

Methods

During 2013–2014, we recruited 78 workers from six US companies that made BPA or made products with BPA. We quantified BPA in seven urine samples, two full-shift air samples and in pre- and end-shift hand-wipe samples collected from workers over 2 consecutive days. We examined correlations between creatinine-corrected urinary concentrations of total BPA (total BPA_CR) and BPA levels in air and hand wipes using Pearson's correlation coefficient. We also applied mixed-effects regression models to examine the relationship between total BPA_CR with BPA in air (urine~air model) and with BPA in end-shift hand wipes (urine~hand model), separately and together (urine~air+hand model), after adjusting for covariates.

Results

End-shift total BPA_CR strongly correlated with BPA in air (r_p = 0.79, P < 0.0001) and nearly as strongly with BPA in end-shift hand wipes (r_p = 0.75, P < 0.0001). In mixed-effect models, BPA air concentration and end-shift hand-wipe BPA level were significantly and positively associated with end-shift total BPA_CR (P < 0.0001 each). We found a significant effect of the Day 1 BPA air concentration on Day 2 total BPA_CR (P = 0.0104). When BPA air concentration and end-shift hand-wipe BPA level were in the same model, the air concentration (P < 0.0001) was more significant than the hand-wipe level (P = 0.0106).

Conclusion

BPA levels in air and end-shift hand wipes strongly correlated with total BPA_CR, suggesting that both inhalation and dermal contract were likely exposure routes; however, inhalation, on average, appeared to be a more dominant exposure route than dermal contact for these manufacturing workers.

Carbonaceous Monolithic Multi-Channel Denuders as Vapour–Particle Partitioning Tools for the Occupational Sampling of Semi-Volatile Organic Compounds

Abstract

Denuders are gas–particle partitioning tools and can be used in combination with filters and adsorbers for phase-separated collection of hazardous semi-volatile organic compound (SVOC) aerosols. Here, we investigated the suitability of carbonaceous monolithic multi-channel denuders for this approach. Particle transmission efficiency through the denuders was investigated using particles of polystyrene latex (PSL) and droplets of n-hexadecane and diethylene glycol. The time-dependent vapour collection efficiency was analysed for n-hexadecane and diethylene glycol vapours and also compared to calculated predictions. Our measurements showed an averaged transmission efficiency of 97 ± 4.4% for PSL particles with diameters of 0.51, 0.99, 1.93, and 3.00 µm. Measurements with one denuder and 1.08, 1.98, and 2.97 µm particles consisting of n-hexadecane or diethylene glycol resulted in an averaged transmission efficiency of 99 ± 6.5%. Regarding the vapour collection efficiency at a flow rate of 5 l min⁻¹, n-hexadecane vapour could be adsorbed to a similar extent (91 ± 1.4% for one denuder, 98 ± 0.3% for two denuders) as diethylene glycol vapour (93 ± 1.8% for one denuder, 97 ± 0.9% for two denuders). The comparison between experimental and theoretical vapour collection efficiencies revealed differences around 2.8% for n-hexadecane and around 12.3% for diethylene glycol. The results show that the tested denuders can be used as vapour collection tools for SVOCs, and can be integrated in currently used personal air samplers for separated vapour and particle collection.

Pemetrexed anaphylaxis – an unusual suspect

Publication date: Available online 13 June 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Leonor Carneiro-Leão, Vladyslava Barzylovych, Josefina Cernadas

Efectividad de la fototerapia ultravioleta B de banda estrecha con un esquema bisemanal en el tratamiento de la micosis fungoide estadio temprano en una cohorte de 18 pacientes argentinos

Publication date: Available online 13 June 2018
Source:Actas Dermo-Sifiliográficas
Author(s): D.A. De Luca, E.A. Zambrano, R.L. Galimberti, P.A. Enz

Association between Breslow Thickness and Dermoscopic Findings in Acral Melanoma

Publication date: Available online 13 June 2018
Source:Journal of the American Academy of Dermatology
Author(s): Je-Ho Mun, Gwanghyun Jo, Claudia C. Darmawan, Jin Park, Jung Min Bae, HyunJu Jin, Woo-Il Kim, Hoon-Soo Kim, Hyun-Chang Ko, Byung-Soo Kim, Moon-Bum Kim
BackgroundDermoscopy is a useful tool for the diagnosis of acral melanomas (AM). However, little is known about the influence of tumor thickness on the dermoscopic findings of AM.ObjectiveTo investigate the impact of Breslow thickness (BT) on the dermoscopic patterns of AM.MethodsData on cases of AM on the glabrous skin were collected from four university hospitals. We investigated the frequency of each dermoscopic feature of AM according to the BT. Statistical analysis was performed to investigate the association between the specific dermoscopic patterns and BT.ResultsMultivariable analysis revealed that red (odds ratio [OR] 16.482, 95% confidence interval [CI] 3.605-99.016), blue (OR 7.092; 95% CI 1.707-37.435), and white colors (OR 5.048, 95% CI 1.152-22.897) were more common in AM with BT >2 mm. Regarding patterns, atypical vascular patterns (OR 34.589, 95% CI 6.458-305.852), blue-white veil (OR 9.605, 95% CI 1.971-72.062), and ulcers (OR 5.084, 95% CI 1.145-24.152) were more frequently detected in cases with BT >2 mm.LimitationsA retrospective study design and small sample sizeConclusionThis study showed an association between dermoscopic patterns and tumor thickness among patients with AM. Dermoscopy can be a useful adjuvant tool in predicting BT in AM.

Noninvasive Assessment of Hemodynamic Stress Distribution after Indirect Revascularization for Pediatric Moyamoya Vasculopathy [PEDIATRICS]

BACKGROUND AND PURPOSE:

Indirect revascularization surgery is an effective treatment in children with Moyamoya vasculopathy. In the present study, we hypothesized that DSC-PWI may reliably assess the evolution of CBF-related parameters after revascularization surgery, monitoring the outcome of surgical pediatric patients with Moyamoya vasculopathy. Thus, we aimed to evaluate differences in DSC-PWI parameters, including the hemodynamic stress distribution, in surgical and nonsurgical children with Moyamoya vasculopathy and to correlate them with long-term postoperative outcome.

MATERIALS AND METHODS:

Pre- and postoperative DSC parameters of 28 patients (16 females; mean age, 5.5 ± 4.8 years) treated with indirect revascularization were compared with those obtained at 2 time points in 10 nonsurgical patients (6 females; mean age, 6.9 ± 4.7 years). We calculated 4 normalized CBF-related parameters and their percentage variance: mean normalized CBF of the MCA territory, mean normalized CBF of the proximal MCA territory, mean normalized CBF of cortical the MCA territory, and hemodynamic stress distribution. The relationship between perfusion parameters and postoperative outcomes (poor, fair, good, excellent) was explored using 1-way analysis of covariance (P < .05).

RESULTS:

A significant decrease of the mean normalized CBF of the proximal MCA territory and hemodynamic stress distribution and an increase of the mean normalized CBF of the cortical MCA territory were observed after revascularization surgery (P < .001). No variations were observed in nonsurgical children. Postoperative hemodynamic stress distribution and its percentage change were significantly different in outcome groups (P < .001).

CONCLUSIONS:

DSC-PWI indices show postoperative hemodynamic changes that correlate with clinical outcome after revascularization surgery in children with Moyamoya disease.

Targeting the Clot in Acute Stroke [letter]

Surpass Streamline Flow-Diverter Embolization Device for Treatment of Iatrogenic and Traumatic Internal Carotid Artery Injuries [INTERVENTIONAL]

SUMMARY:

Iatrogenic and traumatic cerebral internal carotid artery injuries are uncommon but potentially lethal complications. Direct surgical repair of ICA injuries may be difficult in an acute setting. However, endovascular treatment with a flow-diverter embolization device is a feasible alternative technique that we experienced. In this clinical report, we describe demographic data, radiographic images, lesion characteristics, endovascular procedure notes, postprocedural hospital course, and follow-up digital subtraction angiography of 5 patients. At least 6-month follow-up was available in all patients without occurrence of rebleeding and other complications.

Consensus Needed for Noncontrast CT Markers in Intracerebral Hemorrhage [letter]

Clinical Outcomes of Endovascular Treatment within 24 Hours in Patients with Mild Ischemic Stroke and Perfusion Imaging Selection [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Endovascular thrombectomy has been accepted as the standard of care for patients with acute ischemic stroke. Our aim was to investigate the clinical outcomes of patients with mild ischemic stroke with acute proximal large-vessel occlusion after endovascular treatment within 24 hours of symptom onset.

MATERIALS AND METHODS:

Between January 2014 and August 2017, ninety-three Chinese patients with mild ischemic stroke (NIHSS scores, 0–8) and large-vessel occlusion with endovascular treatment were retrospectively enrolled from 7 comprehensive stroke centers. They were divided into 2 groups: ≤6 hours and 6–24 hours from symptom onset to groin puncture. We analyzed their modified Rankin Scale scores at 90 days, symptomatic intracranial hemorrhage at 48 hours, and mortality during 90 days. Multivariable linear regression analysis was used to identify predictors for NIHSS shift after discharge.

RESULTS:

Twenty-nine patients received endovascular treatment within 6–24 hours after symptom onset and had an imaging mismatch based on perfusion CT or diffusion-weighted MR imaging. There were no substantial differences between the 2 groups in 90-day functional independence (P = .54) and the risks of the combination of symptomatic intracranial hemorrhage and death (P = .72). Two significant indicators of NIHSS shift were 48-hour symptomatic intracranial hemorrhage (unstandardized β = 7.28; 95% CI, 3.48–11.1; P < .001) and baseline systolic blood pressure (unstandardized β = 0.08; 95% CI, 0.03–0.14; P = .005).

CONCLUSIONS:

Patients with mild ischemic stroke and large-vessel occlusion in the anterior circulation, an imaging mismatch, and endovascular treatment within 6–24 hours of initial symptoms showed no heterogeneity in the efficacy and safety outcome compared with those treated ≤6 hours from symptom onset.

Increasing the Accuracy of Optic Nerve Measurement Using 3D Volumetry [letter]

Cavitary Plaques in Otospongiosis: CT Findings and Clinical Implications [HEAD & NECK]

BACKGROUND AND PURPOSE:

Cavitary plaques have been reported as a manifestation of otospongiosis. They have been related to third window manifestations, complications during cochlear implantation, and sensorineural hearing loss. However, their etiology and clinical implications are not entirely understood. Our purpose was to determine the prevalence, imaging findings, and clinical implications of cavitary plaques in otospongiosis.

MATERIALS AND METHODS:

We identified patients with otospongiosis at a tertiary care academic medical center from January 2012 to April 2017. Cross-sectional CT images and clinical records of 47 patients (89 temporal bones) were evaluated for the presence, location, and imaging features of cavitary and noncavitary otospongiotic plaques, as well as clinical symptoms and complications in those who underwent cochlear implantation.

RESULTS:

Noncavitary otospongiotic plaques were present in 86 (97%) temporal bones and cavitary plaques in 30 (35%). Cavitary plaques predominated with increasing age (mean age, 59 years; P = .058), mostly involving the anteroinferior wall of the internal auditory canal (P = .003), and their presence was not associated with a higher grade of otospongiosis by imaging (P = .664) or with a specific type of hearing loss (P = .365). No patients with cavitary plaques had third window manifestations, and those with a history of cochlear implantation (n = 6) did not have complications during the procedure.

CONCLUSIONS:

Cavitary plaques occurred in one-third of patients with otospongiosis. Typically, they occurred in the anteroinferior wall of the internal auditory canal. There was no correlation with the degree of otospongiosis, type of hearing loss, or surgical complications. Cavitary plaques tended to present in older patients.

REPLY: [reply]

CSF Pressure Change in Relation to Opening Pressure and CSF Volume Removed [SPINE]

BACKGROUND AND PURPOSE:

Idiopathic intracranial hypertension is a complex neurologic disorder resulting from increased intracranial pressure. Our aim was to determine whether a correlation exists between the CSF pressure-volume relationship, specifically the craniospinal elastance and pressure-volume index, in patients with idiopathic intracranial hypertension and whether opening pressure affects this relationship.

MATERIALS AND METHODS:

Lumbar punctures performed for suspected idiopathic intracranial hypertension from 2006 to 2017 were identified. Opening and closing pressures, CSF volume removed, and clinical diagnosis of idiopathic intracranial hypertension were obtained from the medical records. The craniospinal elastance (pressure change per milliliter of CSF removed) and pressure-volume index were calculated, and the Pearson correlation coefficients between both the craniospinal elastance and pressure-volume index and opening pressure were determined. Linear regression models of craniospinal elastance and the pressure-volume index and interaction terms with opening pressure were assessed for covariate influence on this association.

RESULTS:

One hundred sixteen patients were included in the final analysis. The mean craniospinal elastance according to opening pressure group was 0.52 ± 0.18 for <20 cm H₂O, 0.57 ± 0.20 for 20–29 cm H₂O, 0.91 ± 0.28 for 30–39 cm H₂O, and 1.20 ± 0.25 for ≥40 cm H₂O. There was a positive linear association between opening pressure and craniospinal elastance with a 0.28 cm H₂O/mL increase in craniospinal elastance (standard error = 0.03, P < .001) for every 10 cm H₂O increase in opening pressure. Of the covariables analyzed, only age older than 50 years and total volume of CSF removed affected this association.

CONCLUSIONS:

As opening pressure increases, the craniospinal elastance increases in a linear fashion while the pressure-volume index decreases. Further studies are needed to determine whether these changes relate to the underlying pathophysiology of idiopathic intracranial hypertension or simply represent established CSF volume pressure dynamics.

[other]

Multicentric Experience in Distal-to-Proximal Revascularization of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Internal carotid dissection is a frequent cause of ischemic stroke in young adults. It may cause tandem occlusions in which cervical carotid obstruction is associated with intracranial proximal vessel occlusion. To date, no consensus has emerged concerning endovascular treatment strategy. Our aim was to evaluate our endovascular "distal-to-proximal" strategy in the treatment of this stroke subtype in the first large multicentric cohort.

MATERIALS AND METHODS:

Prospectively managed stroke data bases from 2 separate centers were retrospectively studied between 2009 and 2014 for records of tandem occlusions related to internal carotid dissection. Atheromatous tandem occlusions were excluded. The first step in the revascularization procedure was intracranial thrombectomy. Then, cervical carotid stent placement was performed depending on the functionality of the circle of Willis and the persistence of residual cervical ICA occlusion, severe stenosis, or thrombus apposition. Efficiency, complications, and radiologic and clinical outcomes were recorded.

RESULTS:

Thirty-four patients presenting with tandem occlusion stroke secondary to internal carotid dissection were treated during the study period. The mean age was 52.5 years, the mean initial NIHSS score was 17.29 ± 6.23, and the mean delay between onset and groin puncture was 3.58 ± 1.1 hours. Recanalization TICI 2b/3 was obtained in 21 cases (62%). Fifteen patients underwent cervical carotid stent placement. There was no recurrence of ipsilateral stroke in the nonstented subgroup. Twenty-one patients (67.65%) had a favorable clinical outcome after 3 months.

CONCLUSIONS:

Endovascular treatment of internal carotid dissection–related tandem occlusion stroke using the distal-to-proximal recanalization strategy appears to be feasible, with low complication rates and considerable rates of successful recanalization.

What Have We Learned from Perfusion MRI in Multiple Sclerosis? [ADULT BRAIN]

SUMMARY:

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.

Anatomic and Angiographic Analyses of Ophthalmic Artery Collaterals in Moyamoya Disease [EXTRACRANIAL VASCULAR]

BACKGROUND AND PURPOSE:

Moyamoya disease is a progressive neurovascular pathology defined by steno-occlusive disease of the distal internal carotid artery and associated with the development of compensatory vascular collaterals. The etiology and exact anatomy of vascular collaterals have not been extensively studied. The aim of this study was to describe the anatomy of collaterals developed between the ophthalmic artery and the anterior cerebral artery in a Moyamoya population.

MATERIALS AND METHODS:

All patients treated for Moyamoya disease from 2004 to 2016 in 4 neurosurgical centers with available cerebral digital subtraction angiography were included. Sixty-three cases were evaluated, and only 38 met the inclusion criteria. Two patients had a unilateral cervical internal carotid occlusion that limited analysis of ophthalmic artery collaterals to one hemisphere. This study is consequently based on the analysis of 74 cerebral hemispheres.

RESULTS:

Thirty-eight patients fulfilled the inclusion criteria. The most frequently encountered anastomosis between the ophthalmic artery and cerebral artery was a branch of the anterior ethmoidal artery (31.1%, 23 hemispheres). In case of proximal stenosis of the anterior cerebral artery, a collateral from the posterior ethmoidal artery could be visualized (16 hemispheres, 21.6%). One case (1.4%) of anastomosis between the lacrimal artery and the middle meningeal artery that permitted the vascularization of a middle cerebral artery territory was also noted.

CONCLUSIONS:

Collaterals from the ophthalmic artery are frequent in Moyamoya disease. Their development depends on the perfusion needs of the anterior cerebral artery territories. Three other systems of compensation could be present (callosal circle, leptomeningeal anastomosis, and duro-pial anastomoses).

Who's Contributing Most to American Neuroscience Journals: American or Foreign Authors? [research-article]

BACKGROUND AND PURPOSE:

With globalization, the contributions of authors from abroad to the American published literature has increased. We sought to determine the changes with time in the proportional contributions of American and non-American authors in the American neurosciences literature. We hypothesized the following: 1) During the past 21 years, manuscript contributions of American institutions have proportionally decreased in neuroradiology, more than in neurosurgery or neurology; 2) contributions of Asian institutions have affected neuroradiology more than neurosurgery and neurology; and 3) American articles garner more citations.

MATERIALS AND METHODS:

We reviewed the May issues of 2 of the highest impact American-based neurology, neurosurgery, and neuroradiology journals published from 1997 to 2017. We counted the number of articles published by nation based on the institution of origin. We looked at trends across time and compared neurology, neurosurgery, and neuroradiology journals. We also gathered data on the number of citations of each article by nationality.

RESULTS:

We reviewed 3025 articles. There was a significantly lower ratio of American to non-American authorship in neuroradiology versus neurology/neurosurgery journals (odds ratio = 0.70; 95% confidence interval, 0.60–0.82). There was a significantly decreasing trend in American authorship across the 21 years in neuroradiology. Of the countries outside the United States, Japan contributed most for neuroradiology and neurosurgery journals, and the UK, for neurology. American-authored articles were cited, on average, 1.25 times more frequently than non-American-authored articles.

CONCLUSIONS:

Non-American contributions have impacted neuroradiology more than other clinical neuroscience fields with Asian authorship showing the greatest impact. That impact is growing, and the causes are manifold. Nonetheless American-authored articles are cited more.

Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies [PEDIATRICS]

BACKGROUND AND PURPOSE:

Neuroimaging features in neonates with RASopathies are rarely reported, and to date, there are no neuroimaging studies conducted in this population. Our aim was to investigate the occurrence of supratentorial and posterior fossa abnormalities on brain MRIs of neonates with a RASopathy.

MATERIALS AND METHODS:

An observational case-control study of neonates with a confirmed RASopathy was conducted. The presence of an intraventricular and/or parenchymal hemorrhage and punctate white matter lesions and assessments of the splenium of the corpus callosum, gyrification of the cortical gray matter, and enlargement of the extracerebral space were noted. The vermis height, transverse cerebellar diameter, cranial base angle, tentorial angle, and infratentorial angle were measured.

RESULTS:

We reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1 (P < .001, for each). The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1 (P = .01, P < .001, and P = .001, respectively).

CONCLUSIONS:

Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. This study provides novel neuroimaging findings on supratentorial and posterior fossa abnormalities in neonates with a RASopathy.

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors.

MATERIALS AND METHODS:

DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo–EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity.

RESULTS:

For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%).

CONCLUSIONS:

By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

Postnatal Brain Growth Assessed by Sequential Cranial Ultrasonography in Infants Born <30 Weeks' Gestational Age [PEDIATRICS]

BACKGROUND AND PURPOSE:

Brain growth in the early postnatal period following preterm birth has not been well described. This study of infants born at <30 weeks' gestational age and without major brain injury aimed to accomplish the following: 1) assess the reproducibility of linear measures made from cranial ultrasonography, 2) evaluate brain growth using sequential cranial ultrasonography linear measures from birth to term-equivalent age, and 3) explore perinatal predictors of postnatal brain growth.

MATERIALS AND METHODS:

Participants comprised 144 infants born at <30 weeks' gestational age at a single center between January 2011 and December 2013. Infants with major brain injury seen on cranial ultrasonography or congenital or chromosomal abnormalities were excluded. Brain tissue and fluid spaces were measured from cranial ultrasonography performed as part of routine clinical care. Brain growth was assessed in 3 time intervals: <7, 7–27, and >27 days' postnatal age. Data were analyzed using intraclass correlation coefficients and mixed-effects regression.

RESULTS:

A total of 429 scans were assessed for 144 infants. Several linear measures showed excellent reproducibility. All measures of brain tissue increased with postnatal age, except for the biparietal diameter, which decreased within the first postnatal week and increased thereafter. Gestational age of ≥28 weeks at birth was associated with slower growth of the biparietal diameter and ventricular width compared with gestational age of <28 weeks. Postnatal corticosteroid administration was associated with slower growth of the corpus callosum length, transcerebellar diameter, and vermis height. Sepsis and necrotizing enterocolitis were associated with slower growth of the transcerebellar diameter.

CONCLUSIONS:

Postnatal brain growth in infants born at <30 weeks' gestational age can be evaluated using sequential linear measures made from routine cranial ultrasonography and is associated with perinatal predictors of long-term development.

Edge Contrast of the FLAIR Hyperintense Region Predicts Survival in Patients with High-Grade Gliomas following Treatment with Bevacizumab [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Treatment with bevacizumab is standard of care for recurrent high-grade gliomas; however, monitoring response to treatment following bevacizumab remains a challenge. The purpose of this study was to determine whether quantifying the sharpness of the fluid-attenuated inversion recovery hyperintense border using a measure derived from texture analysis—edge contrast—improves the evaluation of response to bevacizumab in patients with high-grade gliomas.

MATERIALS AND METHODS:

MRIs were evaluated in 33 patients with high-grade gliomas before and after the initiation of bevacizumab. Volumes of interest within the FLAIR hyperintense region were segmented. Edge contrast magnitude for each VOI was extracted using gradients of the 3D FLAIR images. Cox proportional hazards models were generated to determine the relationship between edge contrast and progression-free survival/overall survival using age and the extent of surgical resection as covariates.

RESULTS:

After bevacizumab, lower edge contrast of the FLAIR hyperintense region was associated with poorer progression-free survival (P = .009) and overall survival (P = .022) among patients with high-grade gliomas. Kaplan-Meier curves revealed that edge contrast cutoff significantly stratified patients for both progression-free survival (log-rank ² = 8.3, P = .003) and overall survival (log-rank ² = 5.5, P = .019).

CONCLUSIONS:

Texture analysis using edge contrast of the FLAIR hyperintense region may be an important predictive indicator in patients with high-grade gliomas following treatment with bevacizumab. Specifically, low FLAIR edge contrast may partially reflect areas of early tumor infiltration. This study adds to a growing body of literature proposing that quantifying features may be important for determining outcomes in patients with high-grade gliomas.

Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke [research-article]

Postcontrast T1 Mapping for Differential Diagnosis of Recurrence and Radionecrosis after Gamma Knife Radiosurgery for Brain Metastasis [ADULT BRAIN]

BACKGROUND AND PURPOSE:

The differential diagnosis of radionecrosis and tumor recurrence in brain metastases is challenging. We investigated the diagnostic efficiency of postcontrast T1 mapping in solving this problem.

MATERIALS AND METHODS:

Between March 2016 and June 2017, fifty-six patients with brain metastases who underwent contrast-enhanced cerebral T1 mapping were recruited for this prospective study. The findings revealed new enhancement after gamma knife radiosurgery. The subjects were assigned to radionecrosis and recurrence groups based on follow-up (median, 11.5 months) and histopathologic results. T1 values of lesions 5 (T1_5min) and 60 (T1_60min) minutes after administration of contrast agent and their difference (T1_differ) were compared between the 2 groups with the 2-tailed Mann-Whitney U test. Receiver operating characteristic curves were used to determine the optimum cutoff values for differential diagnosis.

RESULTS:

There were significant differences between the 2 groups in T1_5min, T1_60min, and T1_differ values (P = .012, P = .004, and P < .001, respectively). Relative to T1_5min and T1_60min, T1_differ exhibited greater sensitivity and specificity (P < .001, respectively) in identifying radionecrosis. The optimum T1_differ value for differential diagnosis was 71.1 ms (area under the curve = 0.97; 95% CI, 0.93–1.00), with sensitivity and specificity of 81.5% and 96.5%, respectively.

CONCLUSIONS:

Postcontrast T1 mapping is optimal for the differential diagnosis of radionecrosis and tumor recurrence. Among T1 parameters, T1_differ is the most powerful parameter for differential diagnosis. Advantages in terms of quantitative analysis and high resolution portend the wide use of postcontrast T1 mapping in the future.

Skin Paddles Improve Muscle Flap Salvage Rates After Microvascular Compromise in Lower Extremity Reconstruction

Purpose Free tissue transfer after lower extremity trauma is associated with notoriously high complication rates. Theoretically, the inclusion of a cutaneous paddle on muscle free flaps may improve clinical flap monitoring. The effect of skin paddle presence on muscle free flap salvage outcomes after take-back was examined. Methods Retrospective query of our institutional free-flap registry (1979–2016) identified 362 muscle-based flaps performed for soft tissue coverage after below-knee trauma. Primary outcome measures were perioperative complications, specifically take-back indications, timing, and flap salvage rates. Univariate and multivariate regression analyses were performed where appropriate. Results The most common flaps were latissimus dorsi (166; 45.9%), rectus abdominis (123; 34%), and gracilis (42; 11.6%) with 90 flaps (24.9%) including skin paddles. Take-backs for vascular compromise occurred in 44 flaps (12.2%), of which 39% contained a skin paddle while 61% did not. Overall salvage rate was 20.5%, with 31.8% partial failures and 47.7% total flap losses. Muscle flaps with skin paddles were more likely to return to the operating room within 48 hours postoperatively than those without (57.1% vs 18.2%, P = 0.036). After take-back, significantly more muscle flaps with skin paddles were salvaged compared with muscle flaps without paddles (35.7% vs 4.5%, P = 0.024). Similarly, more muscle-only flaps after take-back failed compared with their counterparts with skin paddles (95.5% vs 65.3%, P = 0.024). Conclusions Muscle flaps with a cutaneous paddle were associated with earlier return to the operating room and more successful flap salvage after take-back compared with muscle-only flaps. These findings suggest that skin paddle presence may improve clinical flap monitoring and promote recognition and treatment of microvascular compromise in lower extremity reconstruction.

A Cyst Compressing the Ulnar Nerve Motor Branch: Ultrasonographic Diagnosis of a Tricking Neuropathy

No abstract available

Correction of Tuberous Nipple Areolar Complex Deformity in Gynecomastia: The Deformity That Can Get Forgotten

The desired end point of surgical reduction of gynecomastia is a masculine breast appearance and symmetry. This article concentrates on the tuberous deformity of the nipple areolar complex (NAC) that can present in gynecomastia and is sometimes overlooked at surgical correction. This deformity can be corrected at primary surgery if it is recognized preoperatively. If missed, or not adequately corrected, the postoperative result of primary reduction may be deemed incomplete by the patient and they will request revision. The deformity involves overprojection of the NAC in an anteroposterior direction, yet the base diameter may be close to normal. Correction involves reduction of the herniated breast bud, excision of excess areolar tissue, and careful radial scoring to flatten the NAC to a normal level of projection. For the NAC to have a masculine appearance, the areolae need to be symmetrical, of normal male size, and slightly oval in a transverse direction. The projection of both areola and nipple needs to be low, but present: not flattened. This article presents an operative technique to address primary or residual tuberous NAC deformity in the treatment of gynecomastia.

Computed Tomographic Angiography Used for Localization of the Cutaneous Perforators and Selection of Anterolateral Thigh Flap “Bail-Out” Branches

Background The purpose of this study was to evaluate the territory supplied by the lateral circumflex femoral artery for the consistency of a proximal perforator that could be used as an alternative pedicle for the anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of the perforator used to develop the initial surgical plan. It is hypothesized that a consistent "bail-out" perforator supplying the proximal thigh would facilitate a simpler anterolateral thigh flap harvest, with minimal modification to flap design. Methods Computed tomographic images of 9 fresh cadavers were imported using Materialize's Interactive Medical Imaging Control System software to create surface-rendered 3-dimensional reconstructions of 15 lower limbs. Perforators emerging proximally and laterally to a 3-cm radius circle drawn at the midpoint of the anterior superior iliac spine and superolateral patella were considered potential bail-out perforators and evaluated for their number emerging diameter, length, course, and location relative to the anterior superior iliac spine. Results An average of 2.9 ± 1.8 perforators per limb were identified. Mean pedicle length was 111 ± 20 mm, measured from the origin in the lateral circumflex femoral artery to where the perforators emerged through the deep fascia directly overlying the thigh muscles. Average diameter at origin in the lateral circumflex femoral artery was 2.8 ± 0.8 mm, and that at emergence through the deep fascia was 1.1 ± 0.3 mm. Vessel course was predominantly musculocutaneous (90%). Conclusions A significant bail-out perforator routinely supplies the proximal anterolateral thigh and may be used as an alternative vascular pedicle for an anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of a perforator identified within the conventional landmarks (3-cm radius circle at the midpoint of the anterior superior iliac spine and superolateral patella).

The Use of Expanded Polytetrafluoroethylene in Short Nose Elongation: Fourteen Years of Clinical Experience

Background Short nose elongation is a relatively common rhinoplasty procedure, especially in Asia. The selection of the adequate graft material is challenging. Previous reports have described the application of expanded polytetrafluoroethylene (ePTFE) for dorsal augmentation rhinoplasty, but studies using ePTFE for nose elongation are lacking. We propose ePTFE as an alternative treatment for short noses, describe the technique, and discuss outcomes, patient selection, and complications based on our 14-year experience. Methods From February 2003 to December 2016, 206 patients with varying degrees of short noses were included in this retrospective study. All patients underwent nose elongation surgery using an ePTFE implant. Nasal lengths before and after surgery were measured using a 3-dimensional simulation technology. Outcomes and complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey. Results Nasal elongation was successfully achieved using ePTFE. Mean increase in nasal length was 4.36 ± 0.85 mm. The mean follow-up period was 13.3 months, ranging from 6 months to 8 years. Follow-up examinations demonstrated stable results. The overall complication rate was 6.8%. Complications included infection, implant extrusion, migration, deviation, visibility, and/or prominence, tissue reaction, and reddening of the nasal skin. Most patients (93.6%) rated their outcome as improved and much improved. Conclusions Nasal elongation using ePTFE implantation is a feasible therapeutic approach for patients with short noses. Reliable outcomes and the absence of donor site morbidity contribute to the high patient acceptance. Meticulous surgical technique and careful patient selection are prerequisites for successful results.

Three-Dimensional Analysis of Mandibular Angle Classification and Aesthetic Evaluation of the Lower Face in Chinese Female Adults

Background Reduction gonioplasty is very popular in East Asia. However, there has been little quantitative criteria for mandibular angle classification or aesthetics. The aim of this study was to investigate the quantitative differences of mandibular angle types and determine the morphologic features of mandibular angle in attractive women. Methods We created a database of skull computed tomography and standardized frontal and lateral photographs of 96 Chinese female adults. Mandibular angle was classified into 3 groups, namely, extraversion, introversion, and healthy group, based on the position of gonion. We used a 5-point Likert scale to quantify attractiveness based on photographs. Those who scored 4 or higher were defined as attractive women. Three types of computed tomography measurements of the mandible were taken, including 4 distances, 4 angles, and 3 proportions. Discriminant analysis was applied to establish a mathematic model for mandibular angle aesthetics evaluation. Results Significant differences were observed between the different types of mandibular angle in lower facial width (Gol-Gor), mandibular angle (Co-Go-Me), and gonion divergence angle (Gol-Me-Gor) (P

Massive Localized Lymphedema: Analysis of Intraoperative Care

Massive localized lymphedema (MLL) is rare, but as the prevalence of obesity in adults rises, it can be foreseen that cases will increase in prevalence. These patients are unable to ambulate and have uncontrollable rash and skin breakdown. Operative management for MLL is offered when nonsurgical measures are ineffective. The surgery can be difficult with ambiguous tissue planes saturated with lymphatic fluid, ill-defined margins, large arteries and dilated veins, and extensive intraoperative fluid and blood loss. We performed a retrospective chart review and analysis with a focus on the intraoperative findings and management in order to provide improved awareness and recommendations for preoperative care. We reviewed the charts of 15 patients with MLL undergoing a total of 17 surgical resections at our institution. Patients were morbidly obese with an average body mass index of 63 kg/m2 and 5.5 other medical comorbidities. Average operative time was 4.5 hours. Operative time showed a moderate correlation with increased blood loss. Operative transfusion averaged approximately 1 U per case, with 12% (2/17) of cases needing additional transfusions following surgery. An increase in operative time correlated with an increase in crystalloid infusion. In conclusion, we recommend close communication between the surgery and anesthesia teams regarding the extent of the resection and potential for fluid resuscitation and transfusions. Preoperative laboratory tests are recommended, as well as type and cross-match prior to the operation to obtain a baseline for intraoperative and postoperative monitoring. Recommendations for intraoperative management include strict input and output monitoring and aggressive fluid resuscitation with appropriate arterial and venous access.

Periumbilical Perforator-Sparing Abdominoplasty in Patients With Abdominal Scars

Abdominoplasty is one of the most common cosmetic surgical procedures. Patients who undergo abdominoplasties with abdominal scars are at an increased risk for skin necrosis and wound breakdown. To prevent further disruption of vascularity, the dissection and mobilization is often limited resulting in a suboptimal esthetic result. The periumbilical perforator-sparing technique allows for vascular preservation and adequate mobilization to produce excellent esthetic results in patients with abdominal scars.

Microvascular Replantation Following Facial Dog Bites in Children: Systematic Review and Management Algorithm

Background Pediatric dog bite injuries account for 1% of emergency department visits per year and represent an underrecognized and underreported public health problem. Reconstructive surgery is frequently utilized, and in the most extreme injuries, microvascular replantation may be considered. We sought to systematically review the available literature on microvascular replantation after facial dog bite injuries in children, with particular attention to perioperative morbidity and long-term follow-up. Methods We reviewed a case of microvascular replantation after a facial dog bite injury in a child from our own institution and conducted a systematic literature search to identify other similar reports. Clinical variables were collected from the reported cases, and descriptive statistics were calculated. A management algorithm was developed from the reviewed published experience. Results We report the youngest child to date in the literature to undergo replantation after a facial dog bite injury. Nineteen other cases were found involving children aged 18 months to 17 years, with follow-up ranging from 2 weeks to 28 years. Anastomosis techniques varied considerably and included both an artery and vein in only 9 (47%) of 19 cases. Venous congestion was nearly universal, and multimodal techniques were used until native venous outflow was reestablished. Blood transfusion was common, but intensive care unit utilization was not frequently reported. Long-term outcomes were excellent, with growth of the replanted part and recovery of function; however, minor revision procedures were common. Conclusions Microvascular replantation following facial dog bite amputation injuries in the pediatric population is the ultimate step in the reconstructive ladder. Strong consideration should be given to microvascular exploration with involvement of large or whole segments of the lip, nose, or ear; however, parents should be counseled extensively regarding the known morbidity of replantation surgery. With meticulous surgical technique and careful postoperative care, replantation after facial dog bite amputation injuries may successfully achieve dramatic and lasting results for pediatric patients.

Deepithelialized Skin Reduction Preserves Skin and Nipple Perfusion in Immediate Reconstruction of Large and Ptotic Breasts

Background Women with large and/or ptotic breasts are often not considered candidates for nipple-sparing mastectomy (NSM) and/or immediate breast reconstruction given difficulties avoiding ischemic complications and achieving a favorable aesthetic result. We report a novel technique involving deepithelialized skin reduction to simultaneously reduce the skin envelope and preserve perfusion to the skin and nipple in immediate breast reconstruction for women that fit this high-risk anatomic profile. Methods We reviewed cases of NSM and skin-sparing mastectomy (SSM) with immediate implant-based and free autologous reconstruction by a single plastic surgeon from 2013 to 2017. All patients had at least size C cup breasts (>500 g) and/or grade 3 ptosis. Select patients undergoing NSM had devascularization of the nipple-areolar complex (NAC) 1 to 2 months before surgery to promote adaptive circulatory change. After mastectomy, skin reductions were performed via Wise, periareolar, or circumareolar reduction patterns, with infolding of a deepithelialized inferior and periareolar skin flap over a tissue expander or free flap. In NSM, the nipple was advanced superiorly and redirected through a keyhole of deepithelialized skin flap. Results Patients had an average age of 43.6 years and body mass index of 27.7. A total of 33 breasts in 19 patients (14 bilateral, 5 unilateral) underwent deepithelialized skin reduction. There were 14 NSM and 19 SSM. Reconstructions consisted of 13 tissue expanders exchanged to implants and 20 abdominally-based free flaps. Four patients underwent devascularization of the NAC before NSM. Six (18%) breasts had partial thickness flap loss that healed by delayed primary (n = 1) or secondary (n = 5) intention. Four nipples, all in patients without prior NAC devascularization, had ischemic complications (2 epidermolysis, 12.5%; 2 partial necrosis, 12.5%), which all healed by secondary intention with the exception of 1 case of NAC removal. Conclusions Skin reduction with deepithelialization and tissue infolding preserves dermal plexus perfusion and promotes nipple and skin flap survival in immediate implant-based and autologous breast reconstruction after SSM and NSM. This technique can be combined with NAC devascularization to further promote nipple perfusion. Overall, this method offers an acceptable complication rate and the potential to expand the reconstructive options available to women with large and/or ptotic breasts.

Abdominal Wall Reconstruction and Patient Comorbidities

No abstract available

Combined Autologous and Prosthetic Breast Reconstruction: Defining the Upper Limits of Safe Expansion in Obesity

Background Combined latissimus dorsi and prosthetic reconstruction is a useful reconstructive option in patients with a history of breast radiation who are not good candidates for abdominally based autologous reconstruction. One difficulty, particularly in obese patients, is that the thickness of the flap can impair port localization, increasing the risk of inadvertent puncture during expansion. The authors sought to investigate the upper limits of tissue thickness at which tissue expansion can be reliably performed. Methods A cadaveric study was designed in which 2 blinded observers attempted to localize the port of a Mentor CPX-4 expander under tissue 1, 2, 3, 4, 5, and 6 cm thick. Thirty attempts were made per tissue thickness. Results For tissue thicknesses of 1 to 4 cm, the success rate was 100% (k = 1). At 5 cm, the success rate decreased to 86.6% (k = 1); at 6 cm, 43.3% (k = 0.85). Point biserial correlation revealed a negative correlation between tissue thickness and accuracy at a thicknesses of greater than 4 cm (r = −0.55, P 4 cm), Fisher exact test revealed a statistically significant difference between these 2 populations (P

Aesthetic Unit Boundary Approach to Large Fibroadenoma Resection

Background Fibroadenomas are the most common benign breast tumors in adolescents. Surgical excision is indicated when the tumor becomes large or symptomatic. Multiple approaches have been described. However, unsightly scars, excess skin, and breast asymmetry are common challenges after tumor resection. The aims of our study were to describe a concentric circumareolar approach combining the round-block technique and geometric principles in the management of large benign breast tumors. Methods This was a retrospective review of pediatric patients who have undergone excision of large fibroadenoma with concentric circumareolar approach from June 2007 to May 2017. Preoperatively, the excess skin that needed to be resected was marked based on geometric principles. Under general anesthesia, circumareolar deepithelialization of the excess skin and tumor resection were performed. Purse-string suture technique was used to achieve the proper nipple-areola complex size. Results Satisfactory breast symmetry and minimal scarring were achieved in all 6 patients. One patient developed a small seroma, which resolved spontaneously without intervention. Conclusions Concentric circumareolar approach can be used to resect large benign breast tumors while concealing the scar along the aesthetic unit boundary of the breast. The cosmetic outcome and recovery were promising. The approach is simple to execute, highly reproducible, and less dependent on intuition.

Modified Design of Anterolateral Thigh Flap for Total Pharyngolaryngectomy Reconstruction: A Single-Center Experience

Background Defects after total pharyngolaryngectomy for hypopharyngeal cancer often require reconstruction via free tissue transfer. Recently, anterolateral thigh (ALT) flap has become the gold standard in many centers because of its advantages with respect to versatility, minimal donor-site morbidity, good speech quality, and relatively low fistula and anastomotic leakage rates. Moreover, ALT allows 2 surgical teams to work simultaneously. However, the height of the parallelogram in the ALT design for neoesophagus reconstruction is usually set at a minimum of 9.4 cm (circumference, 2πr) for smooth food passage. Because this height exceeds 8 cm, the donor site may not be closed primarily, which highly depends on the patient's body habitus and the skin tone or quality and requires other methods, such as local flap or skin graft for wound closure, which subsequently increase operating time and donor-site complication rate. Objectives Thus, we aimed to construct a simple and modified ALT design that will not only include the advantages described earlier but also provide adequate donor-site primary closure without jeopardizing complication rates. Methods Ten patients with hypopharyngeal cancer underwent reconstructive surgery using our modified ALT design after total pharyngolaryngectomy between 2010 and 2017. Our modified ALT design converts this "classical" shape into a parallelogram so that the height of the modified design is always less than 8 cm, thus allowing for easy primary closure of the wound. Results The donor-site defects of all 10 patients were closed primarily. No donor-site complications and partial or total flap loss were observed. One patient experienced persistent wound infection with dehiscence, for which debridement was performed. The stricture and fistula rates were 10% (n = 1) and 20% (n = 2), respectively. The mean follow-up time is approximately 1 year. Conclusions Minimizing donor-site morbidity is an important goal in reconstructive surgery. Our modified ALT flap design is simple, enabling easy primary closure of the donor-site defect, with improved results for the patient and operators. Furthermore, this design is also suitable for ALT flaps with widths larger than 8 cm.

Prospective Analysis of the Greater Occipital Nerve Location in Patients Undergoing Occipital Nerve Decompression

Background Migraine surgery and onabotulinumtoxinA injections aim to deactivate neurovascular trigger points implicated in chronic headaches. The greater occipital nerve (GON) is a common trigger point. The depth of this nerve has not been previously described. The purpose of this study was to report the intraoperative location, including depth, of the GON in human subjects undergoing migraine surgery. Methods We reviewed records of patients who underwent GON decompression by a single surgeon. Intraoperative measurement of the GON location lateral to midline, inferior to the occipital protuberance, and deep to the skin was collected for 2 previously described positions: where GON (a) enters, "point #2," and (b) exits, "point #3," the semispinalis muscle as it travels from deep to superficial (Plast Reconstr Surg. 2010;126:1563–1572; Plast Reconstr Surg. 2004;113:693–697). Results Thirty-four subjects (60 nerves) were included. The mean depths of the GON were 20 mm (SD, 4) at point no. 3 and 30 mm (SD, 6) at point no. 2. In 26 subjects who underwent bilateral surgery, there was a difference between right and left nerve position lateral to midline at point no. 3 (P = 0.008). Female sex (P = 0.014) and body mass index of 29 kg/m2 or less (P

A Risk-Stratified Comparison of High-Risk Findings in Reduction Mammoplasty

Background Reduction mammoplasty is indicated for symptomatic macromastia or breast asymmetry after contralateral cancer surgery. Previous studies compared the incidence of high-risk lesions in resection specimens between these 2 groups. However, no studies have compared incidental findings in breast reduction specimens based on relative risk of cancer. Our study stratifies lesions by relative risk of malignant progression and compares the frequency of these findings in bilateral versus unilateral reduction mammoplasties. Methods Charts were reviewed from 422 patients undergoing breast reductions by a single surgeon over a 10-year period. Age, procedure, specimen weight, and histologic findings were recorded. Pathologic data were stratified by relative risk of malignant progression and compared between patients with and without cancer histories. Results Three hundred five patients underwent bilateral reduction mammoplasty and 117 patients underwent unilateral reduction mammoplasty over the 10-year period. Bilateral patients had a higher incidence of benign lesions (P = 0.02). Both groups had similar incidences of proliferative lesions (P = 0.48). Unilateral patients had a higher incidence of atypia (P = 0.05) and carcinoma in situ (P

Time to Procedure, Nuclear Imaging and Clinicopathological Characteristics as Predictive Factors for Sentinel Lymph Node Metastasis in Cutaneous Melanoma: A Single-Center Analysis

Objective Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored. Methods Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1–98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size. Results Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P

Reconstruction of Extensive Post–Electric Burn Scalp Defects With Exposed Bones: A Study of 12 Cases

The scalp is a unique part of the human body with respect to its shape and position. It is the part of the body that is usually exposed in its original form, with no covering by any means of clothing. In workplaces, especially in the electrical industry in the area of electrical substations and power transmission lines it is this part of the body that can easily come in contact with high tension electrical wires. Others who can be prone to suffer such injuries are pedestrians, people working on heights, ladies hanging clothes on terraces. This case series includes 12 patients who sustained high-voltage electric burn injury to the scalp. Of the reconstructive options used, 2 were free flaps, 1 was a distant flap, and 9 were local flaps. Of the 2 free flaps, there was loss of 1 free flap due to thrombosis, which was later reconstructed with extracorporeal radial forearm flap.Of the 9 local flaps, therewas partial flap necrosis in 2 cases, which required debridement and the wounrds healed secondarily. There was recurrent osteomyelitis in 1 patient who underwent sequestrectomy. In conclusion, the results obtained, in all the patients, were satisfactory without necessitating a bony reconstruction.

Improving Senescent Wound Healing With Local and Systemic Therapies

The population is aging, and the prevalence of chronic wounds is increasing. Because neovascularization is essential for tissue repair and both local and systemic factors affect new blood vessel formation, we hypothesize that altering either pathway would reciprocally enhance wound healing in the aged. To test this hypothesis, p53 was locally suppressed and endothelial progenitor cells (EPCs) were systemically mobilized in a murine model of senescent wound healing. Bilateral 6-mm full-thickness stented wounds were made on the dorsum of Zmpste24−/− mice. Animals received weekly topical p53 small interfering RNA (siRNA) (n = 25), weekly topical nonsense siRNA (n = 25), daily subcutaneous AMD3100 injections (n = 25), or daily subcutaneous saline injections (n = 25). Wounds were photographically assessed and harvested for reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunostaining over 40 days. Circulating EPC levels were measured using fluorescence-activated cell sorting analysis. Local p53 siRNA significantly improved Zmpste24−/− wound healing (18 ± 2 vs 40 ± 3 days; P ≤ 0.0001). p53 siRNA significantly increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Local p53 siRNA also significantly increased the number of circulating EPCs (8 ± 0.2% vs 2.6 ± 0.1%; P ≤ 0.0001). AMD3100 treatment also significantly improved wound healing (20 ± 2 vs 40 ± 3 days; P ≤ 0.0001) and increased EPCs mobilization (7.8 ± 0.4% vs 2.6 ± 0.1%; P ≤ 0.0001). In addition, systemic AMD3100 increased local provasculogenic factors (hypoxia-inducible factor 1 α, stromal cell-derived factor 1 α, and vascular endothelial growth factor; P ≤ 0.05) and decreased local proapoptotic factors (p53, PUMA, and Bax; P ≤ 0.05). Both treatments significantly increased the number of blood vessels in the wound bed (P ≤ 0.0001). The marked delay in Zmpste24−/− wound healing is significantly improved by local (p53 siRNA) and systemic (AMD3100) treatments. The resulting decrease in proapoptotic factors and increase in provasculogenic factors in the wound bed as well as the increased level of circulating EPCs appear to reverse age-related wound healing impairment by enhancing wound neovascularization.

Kinetics of atmospheric reactions of 4-chloro-1-butene

Abstract

Chloroalkenes are among the important anthropogenic organic compounds emitted in the atmosphere as a result of their wide use in synthetic processes in industry. Despite their well-known adverse effects on human health and air quality, the chemistry of these chloroalkenes remains poorly explored. In this work, reactions of 4-chloro-1-butene (CBE), a representative example of chloroalkenes, with O₃, OH, NO₃, and Cl are investigated in a 100-L Teflon reaction chamber equipped with gas chromatography-flame ionization detector (GC-FID). The absolute rate method was used for the reaction with O₃ while the relative rate method was used for reactions with OH, NO₃, and Cl. The following rate constants were obtained at room temperature (298 ± 2) K and atmospheric pressure: (3.96 ± 0.43) × 10⁻¹⁸, (2.63 ± 0.96) × 10⁻¹¹, (4.48 ± 1.23) × 10⁻¹⁵, and (2.35 ± 0.90) × 10⁻¹⁰ cm³ molecule⁻¹ s⁻¹, for reactions with O₃, OH, NO₃, and Cl, respectively. Atmospheric lifetimes of CBE calculated from rate constants of the different reactions obtained in this work showed that reaction with OH is the main loss process for CBE, while in coastal areas and in the marine boundary layer, the CBE loss by Cl reaction becomes important. Estimation of the value of the photochemical ozone creation potential (POCP) indicated that CBE has a large ozone formation potential. The present work underlines the need for further studies on the atmospheric chemistry of chlorinated VOCs.

The different effects of natural pyrethrins and beta -cypermethrin on human hepatocyte QSG7701 cells by ROS-mediated oxidative damage

Abstract

With the widespread use of natural pyrethrins and pyrethroids to defend pest insects, people had the sustained interest in the potential risk to environment and human health. However, the research about natural pyrethrins and beta-cypermethrin induction of cytotoxicity is still seldom. This study is about the cytotoxic effects of these on human non-target cells in vitro. The cytotoxic effect of natural pyrethrins and beta-cypermethrin on QSG7701 cells were researched by using various bioassays in vitro. The results suggested that with the natural pyrethrin concentration increased, the viability of QSG7701 cells were inhibited increasingly, and the IC₅₀ value as calculated was approximately 42.54 and 18.68 μg/mL after the cells were treated 24 and 48 h. The proliferative potential of QSG7701 cells treated with 40 μg/mL natural pyrethrins 6 and 12 h was decreased by 67.44 and 94.74%, dramatic enhancement ROS, collapse of mitochondrial membrane potential, DNA exhibit severity of impairment, and chromatin DNA condensation. However, beta-cypermethrin has lower toxicity than natural pyrethrins. The IC₅₀ values of beta-cypermethrin were all > 80 μg/mL, and the colony formation expression was decreased by 15.26 and 19.09%, which implied that natural pyrethrins are more significantly cytotoxic and potentially genotoxic to human hepatocyte cells.

Use of Dual skin paddles Anterolateral Thigh Perforator flaps in Reconstruction of complex defect of the foot and ankle

Publication date: Available online 12 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Liming Qing, Pangfeng Wu, Fang Yu, Zhengbing Zhou, Juyu Tang
BackgroundComplex soft tissue defect around the ankle and foot still was a difficult reconstructive problem for orthopedic and plastic surgeons. This study describes our clinical experience with the application of dual skin paddles anterolateral thigh perforator (ALTP) flap for reconstruction of complex defects around the ankle and foot.Methods: From June 2010 to June 2015, we retrospectively analyzed 15 patients with complex defects in the ankle and foot. Three types of soft-tissue defects include: irregular defect (n=1), nonadjacent defect (n=4) and extensive defect (n=10). All patients in this series had exposure of underlying vital structures including vessels, nerves, bones, and tendons. All patients in this series underwent reconstruction with the dual skin paddles ALTP flap.Results: The dual skin paddles ALTP flaps were successfully harvested to reconstruct three types of soft tissue defects in the ankle and foot. All the flaps survived. Only one flap had partial flap necrosis. One case suffered minor wound-edge necrosis. All donor sites were closed directly and healed well. The mean follow-up time was 24.46 (range 12 to 54) months. The average static 2-point discrimination (s2PD) of the flap was 33 (range 27 to 38) mm. The mean visual analogue scale score for the aesthetic appearance of the reconstructed defects was 8.9 (range 8 to 9.5).ConclusionOur experience showed that the dual skin paddles ALTP flap can provide two independent skin paddles for complex defect reconstruction whilst minimizing donor site morbidity. It is a reliable option for reconstruction of complex defects in the ankle and foot.

“High Risk Device Registries: Global Value, Costs, and Sustainable Funding.”

Publication date: Available online 12 June 2018
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Babette E. Becherer, Pauline E.R. Spronk, Marc A.M. Mureau, Stephen Mulgrew, A Graeme B. Perks, Birgit Stark, Andrea L. Pusic, David B. Lumenta, Ingrid Hopper, Rodney D. Cooter, Hinne A. Rakhorst
BackgroundWell-designed implant registries have been shown to be a worthwhile investment, from both a health and economic perspective. However, many registries do not attain desirable capture rates or lack sufficient funding, potentially leading to premature termination. This study aims to provide information about rarely discussed, yet pivotal topics regarding the long-term survival of implant registries, focusing on costs, funding models, and the role of stakeholders.MethodsWorldwide, relatively recently developed breast device (BD) registries were compared to long-standing, orthopaedic (OD) and cardiovascular device (CD) registries. A standardised questionnaire was sent to the registries' designated representatives with key positions, discussing start-up costs, costs of maintenance, value of investment, governance, stakeholders, funding, and sustainability.ResultsThirteen registries were included, originating from nine countries (seven BD registries, five OD registries, one CD registry). In general, start-up costs were comparable, and younger registries were more expensive to maintain. Numerous stakeholders showed interest in registry outcomes. However, only 50% of the registries reported a sustainable funding structure.ConclusionThis study provides a global perspective on implantable device registries. All registries provided important information, serving three unique purposes by evaluating the quality of healthcare provided, the quality of all registered devices, and processing recall information. Yet, only half of the registries were certain of sustainable funding, and thus their future existence. It is of utmost importance to bring this to the attention of all parties involved.

Clinical and microbiological properties of Staphylococcus lugdunensis skin infections

The Journal of Dermatology, EarlyView.

Case of Gianotti–Crosti syndrome following varicella zoster virus vaccination

The Journal of Dermatology, EarlyView.

Analysis of possible structures of inducible skin‐associated lymphoid tissue in lupus erythematosus profundus

The Journal of Dermatology, EarlyView.

Impact of chronic urticaria on quality of life and work in Japan: Results of a real‐world study

The Journal of Dermatology, EarlyView.

Procalcitonin as a diagnostic indicator for systemic bacterial infections in patients with Stevens–Johnson syndrome/toxic epidermal necrolysis

The Journal of Dermatology, EarlyView.

PCBs risk evaluation, environmental protection, and management: 50-year research and counting for elimination by 2028