Large area fractional laser treatment of mouse skin increases energy expenditure.

Fractional laser (FL) treatment is a common dermatologic procedure that generates arrays of microscopic treatment zones separated by intact tissue, promoting fast wound healing. Using a mouse model, we introduced a large area fractional laser treatment (LAFLT) method to study metabolic effects. Using two laser modalities, ablative FL (AFL) and non-ablative FL (NAFL), and exposing different percentages of mice's total body surface area (TBSA), we followed changes in metabolic parameters in real time using metabolic cages. Additionally, body composition, markers of inflammation, neurohormonal signaling, and browning of adipocytes were investigated. LAFLT, especially in high TBSA groups, had specific metabolic effects such as significantly increased average daily energy expenditure, increased fat mass loss, systemic browning of adipocytes, and inflammatory states, without compromising other organs. The ability of LAFLT to stimulate metabolism in a controlled way could develop into a promising therapeutic treatment to induce positive metabolic changes that replace or augment systemic drugs.

Impact of feeding habits on the development of language-specific processing of phonemes in brain: An event-related potentials study.

Introduction: Infancy is a stage characterized by multiple brain and cognitive changes. In a short time, infants must consolidate a new brain network and develop two important properties for speech comprehension: phonemic normalization and categorical perception. Recent studies have described diet as an essential factor in normal language development, reporting that breastfed infants show an earlier brain maturity and thus a faster cognitive development. Few studies have described a long-term effect of diet on phonological perception. Methods: To explore that effect, we compared the event-related potentials (ERPs) collected during an oddball paradigm (frequent /pa/80%, deviant/ba/20%) of infants fed with breast milk (BF), cow-milk-based formula (MF), and soy-based formula (SF), which were assessed at 3, 6, 9, 12, and 24 months of age [Mean across all age groups: 127 BF infants, Mean (M) 39.6 gestation weeks; 121 MF infants, M = 39.16 gestation weeks; 116 SF infants, M = 39.16 gestation weeks]. Results: Behavioral differences between dietary groups in acoustic comprehension were observed at 24-months of age. The BF group displayed greater scores than the MF and SF groups. In phonological discrimination task, the ERPs analyses showed that SF group had an electrophysiological pattern associated with difficulties in phonological-stimulus awareness [mismatch negativity (MMN)-2 latency in frontal left regions of interest (ROI) and longer MMN-2 latency in temporal right ROI] and less brain maturity than BF and MF groups. The SF group displayed more right-lateralized brain recruitment in phonological processing at 12-months old. Discussion: We conclude that using soy-based formula in a prolonged and frequent manner might trigger a language development different from that observed in the BF or MF groups. The soy-based formula's composition might affect frontal left-brain area development, which is a nodal brain region in phonological-stimuli awareness.

Effects of Early Nutrition Factors on Baseline Neurodevelopment during the First 6 Months of Life: An EEG Study.

Throughout infancy, the brain undergoes rapid changes in structure and function that are sensitive to environmental influences, such as diet. Breastfed (BF) infants score higher on cognitive tests throughout infancy and into adolescence than formula fed (FF) infants, and these differences in neurocognitive development are reflected in higher concentrations of white and grey matter as measured by MRI. To further explore the effect diet has on cognitive development, electroencephalography (EEG) is used as a direct measure of neuronal activity and to assess specific frequency bands associated with cognitive processes. Task-free baseline EEGs were collected from infants fed with human milk (BF), dairy-based formula (MF), or soy-based formula (SF) at 2, 3, 4, 5, and 6 months of age to explore differences in frequency bands in both sensor and source space. Significant global differences in sensor space were seen in beta and gamma bands between BF and SF groups at ages 2 and 6 months, and these differences were further observed through volumetric modeling in source space. We conclude that BF infants exhibit earlier brain maturation reflected in greater power spectral density in these frequency bands.

Effect of Obesity on Arithmetic Processing in Preteens With High and Low Math Skills: An Event-Related Potentials Study.

Preadolescence is an important period for the consolidation of certain arithmetic facts, and the development of problem-solving strategies. Obese subjects seem to have poorer academic performance in math than their normal-weight peers, suggesting a negative effect of obesity on math skills in critical developmental periods. To test this hypothesis, event-related potentials (ERPs) were collected during a delayed-verification math task using simple addition and subtraction problems in obese [above 95th body mass index (BMI) percentile] and non-obese (between 5th and 90th BMI percentile) preteens with different levels of math skill; thirty-one with low math skills (14 obese, mean BMI = 26.40, 9.79 years old; 17 non-obese, BMI = 17.45, 9.76 years old) and thirty-one with high math skills (15 obese, BMI = 26.90, 9.60 years old; 16 non-obese, BMI = 17.13, 9.63 years old). No significant differences between weight groups were observed in task accuracy regardless of their mathematical skill level. For ERPs, electrophysiological differences were found only in the subtraction condition; participants with obesity showed an electrophysiologic pattern associated with a reduced ability to allocate attention resources regardless of their math skill level, these differences were characterized by longer P300 latency than their normal-weight peers. Moreover, the participants with obesity with high math skills displayed hypoactivity in left superior parietal lobule compared with their normal-weight peers. Additionally, obese preteens with low math skills displayed smaller arithmetic N400 amplitude than non-obese participants, reflecting difficulties in retrieving visual, semantic, and lexical information about numbers. We conclude that participants with obesity are less able than their normal-weight peers to deploy their attention regardless of their behavioral performance, which seems to have a greater effect on obese participants with low math skills because they also show problems in the retrieval of solutions from working memory, resulting in a delay in the development of mathematical skills.

The Impostor Phenomenon in Mental Health Professionals: Relationships Among Compassion Fatigue, Burnout, and Compassion Satisfaction.

Imposter phenomenon is defined as a sense of intellectual fraudulence and an inability to internalize success and competency. Although imposter phenomenon has been noted in several populations, literature is sparse that focuses on mental health professionals. In addition, little is known about the relationships between imposter phenomenon, compassion fatigue, and compassion satisfaction for mental health workers. Using a survey design with a convenience sample of 158 mental health workers, this study found that imposter phenomenon was positively associated with compassion fatigue, as well as negatively associated with compassion satisfaction, when controlling for years of work and age. Further, the combination of lower levels of compassion satisfaction and higher levels of burnout predicted higher levels of imposter phenomenon. Implications and preventative measures are discussed.

Effect of obesity on inhibitory control in preadolescents during stop-signal task. An event-related potentials study.

Preadolescence is a period in which structural and functional changes occur in brain network reorganization that relate to the development of executive control functions, particularly in the areas of attention and cognitive inhibition. Obesity has been associated with a deficit in executive functions and behavioral and electrophysiological differences using the go/no-go task (proactive inhibition), but no study has assessed brain-electrical activity using the stop-signal task (reactive inhibition) in this population. Therefore, we hypothesized that obese preadolescents would show less efficiency in reactive inhibition than their same-age non-obese peers. To test this hypothesis, event-related potentials (ERPs) were collected during a stop-signal task and compared between 27 obese preadolescents (mean BMI = 25.9; 9.65 years old) and 29 normal-weight preadolescents (mean BMI = 17.5; 9.60 years old). No significant differences between groups were observed in behavioral responses. As for ERPs, the obese group had an electrophysiological pattern associated with less efficient conflict monitoring during the "no-go" condition (i.e., less modulation of N200 latency based on the experimental condition), differences in attentional allocation in the "go" condition (less modulation of P300a latency based on experimental condition), and difficulties in rule retrieval from working memory associated with the trial-type in both experimental conditions (smaller P300b amplitude). We conclude that obese preadolescents displayed less ability to modulate conflict-monitoring in the "no-go" condition and attention allocation in the "go" condition, evidencing differences between groups in the development of attention and inhibitory control.

Prevalence and predictors of weight loss during induction therapy for childhood acute lymphoblastic leukemia.

OBJECTIVE: Children with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma often experience significant weight gain during induction therapy. However, a subgroup of patients may experience weight loss, which can impact outcomes; thus, identifying and understanding this underrecognized concern is important. Our aim was to identify the prevalence and predictors for weight loss during ALL induction therapy. METHODS: This was a single-institution retrospective study of 187 patients, ages 2 to 20 y, diagnosed with ALL or lymphoblastic lymphoma. We analyzed weight trends during induction therapy and predictors of weight loss. RESULTS: Significant weight loss (≥5%) occurred in 17% of patients. Having high-risk disease, trisomy 21, overweight/obese status at the time of diagnosis, and/or hyperglycemia were positively associated with weight loss and negatively associated with weight gain during induction therapy. CONCLUSION: Future studies should aim to better understand the etiology and importance of weight loss during induction therapy.

Epidermal Neurite Density in Skin Biopsies From Patients With Juvenile Fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) is defined by idiopathic, chronic, widespread musculoskeletal pain. In adults with FM, a metaanalysis of lower-leg skin biopsy demonstrated 45% pooled prevalence of abnormally low epidermal neurite density (END). END < 5th centile of the normal distribution is the consensus diagnostic threshold for small-fiber neuropathy. However, the clinical significance of END findings in FM is unknown. Here, we examine the prevalence of small-fiber pathology in juvenile FM, which has not been studied previously. METHODS: We screened 21 patients aged 13-20 years with FM diagnosed by pediatric rheumatologists. Fifteen meeting the American College of Rheumatology criteria (modified for juvenile FM) underwent lower-leg measurements of END and completed validated questionnaires assessing pain, functional disability, and dysautonomia symptoms. The primary outcome was proportion of FM patients with END < 5th centile of age/sex/race-based laboratory norms. Cases were systematically matched by ethnicity, race, sex, and age to a group of previously biopsied healthy adolescents with selection blinded to biopsy results. All 23 controls matching demographic criteria were included. RESULTS: Among biopsied juvenile FM patients, 53% (8/15) had END < 5th centile vs 4% (1/23) of healthy controls (P < 0.001). Mean patient END was 273/mm2 skin surface (95% CI 198-389) vs 413/mm2 (95% CI 359-467, P < 0.001). As expected, patients with FM reported more functional disability, dysautonomia, and pain than healthy controls. CONCLUSION: Abnormal END reduction is common in adolescents with FM, with similar prevalence in adults with FM. More studies are needed to fully characterize the significance of low END in FM and to elucidate the clinical implications of these findings.

Acute monophasic erythromelalgia pain in five children diagnosed as small-fiber neuropathy.

The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia.

Resting gamma power during the postnatal critical period for GABAergic system development is modulated by infant diet and sex.

Gamma band activity (30-50 Hz) plays an essential role in brain development and function, but neither the early postnatal development nor subject and environmental factors influencing this development have been reported. We documented the development of resting gamma power using high density EEG recordings obtained each month from postnatal month 2 to 6 in 518 healthy infants who were breast-fed (170; 85 boys), fed milk formula (186; 97 boys), or fed soy formula (162; 90 boys). Gamma power was determined for 44 sites distributed over major brain regions and analyses were adjusted for background variables relevant to neurodevelopment. The results show gamma power follows a gradually increasing function across this time period that varies in topographic magnitude and is differentially influenced by subject and environmental variables-among which gestation, head circumference, and infant diet-sex interactions figure most prominently. Relationships between gamma power and standardized measures of infant behavioral development appear to be emerging but are in flux during this time. Since this postnatal period is considered critical in the development of the GABAergic system underlying the generation of gamma activity, the observed findings may reflect organizational changes that will influence the future development of gamma-related behavioral and neurocognitive functions.

Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.

Corneal innervation as a window to peripheral neuropathies.

The cornea receives the densest sensory innervation of the body, which is exclusively from small-fiber nociceptive (pain-sensing) neurons. These are similar to those in the skin of the legs, the standard location for neurodiagnostic skin biopsies used to diagnose small-fiber peripheral polyneuropathies. Many cancer chemotherapy agents cause dose-related, therapy-limiting, sensory-predominant polyneuropathy. Because corneal innervation can be detected non-invasively, it is a potential surrogate biomarker for skin biopsy measurements. Therefore, we compared hindpaw-skin and cornea innervation in mice treated with neurotoxic chemotherapy. Paclitaxel (0, 5, 10, or 20 mg/kg) was administered to C57/Bl6 mice and peri-mortem cornea and skin biopsies were immunolabeled to reveal and permit quantitation of innervation. Both tissues demonstrated dose-dependent, highly correlated (r = 0.66) nerve fiber damage. These findings suggest that the quantification of corneal nerves may provide a useful surrogate marker for skin peripheral innervation.

Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.

Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN-associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P ≤ 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN-diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively.

Clinical inquiries: How useful are autoantibodies in diagnosing thyroid disorders?

They're useful in diagnosing Graves' disease and, to a lesser extent, autoimmune thyroid disease; they can also help predict hypothyroidism. Thyrotropin receptor antibodies (TRAb) may be mildly elevated in a variety of thyroid disorders, but a TRAb level >10 U/L increases the probability of Graves' disease by a moderate to large degree (strength of recommendation [SOR]: cross-sectional study). A positive or negative thyroid peroxidase antibody (TPOAb) test increases or decreases the probability of autoimmune thyroid disease by only a small to moderate degree (SOR: 3 cross-sectional studies). Thyroid-stimulating hormone (TSH) levels >2 mU/L, although still in the normal range, can be followed up with TPOAb testing to determine whether the patient has an increased probability of developing hypothyroidism (SOR: cohort study with a vague hypothyroidism reference standard).

Dermatomal scratching after intramedullary quisqualate injection: correlation with cutaneous denervation.

UNLABELLED: Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation. PERSPECTIVE: This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.