FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels

Abstract

FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca²⁺-imaging experiments, increases in intracellular Ca²⁺ concentrations ([Ca²⁺]_i) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca²⁺]_i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.

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Endurance exercise increases the protein levels of PGC-1α and respiratory chain complexes in mouse skeletal muscle during atorvastatin administration

Abstract

Statins and exercise reduce cardiovascular disease incidence. We investigated whether endurance exercise in mice induces mitochondrial adaptation in skeletal muscle and muscle injury during administration of atorvastatin, a member of the statin medication class. Male C57BL mice were assigned to one of three groups: control (Con), statin (Statin), or statin and exercise (Statin + Ex). Atorvastatin was administered, and exercise performed on a treadmill for 8 weeks. The levels of mitochondria-associated proteins, PGC-1α, and respiratory chain complex, (COX) I–V, in the quadriceps femoris, and serum creatine kinase, a muscle injury marker, were measured. PGC-1α and COX I–V were upregulated in the Statin + Ex group compared to those in the Statin and Con groups; serum creatine kinase levels were similar. Endurance training in mice induced mitochondrial adaptation in skeletal muscle without causing muscle injury, during atorvastatin administration.

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Application of transcutaneous carbon dioxide improves capillary regression of skeletal muscle in hyperglycemia

Abstract

The purpose of the present study was to determine the effects of transcutaneous CO₂ application on the blood flow and capillary architecture of the soleus muscle in rats with streptozotocin (STZ)-induced hyperglycemia. Wistar rats were randomly divided into four groups: control, control + CO₂-treated, STZ-induced hyperglycemia, and STZ-induced hyperglycemia + CO₂-treated groups. Blood flow in soleus muscle increased during the transcutaneous CO₂ exposure, and continued to increase for 30 min after the treatment. In addition, the transcutaneous CO₂ attenuated a decrease in capillary and the expression level of eNOS and VEGF protein, and an increase in the expression level of MDM-2 and TSP-1 protein of soleus muscle due to STZ-induced hyperglycemia. These results indicate that the application of transcutaneous CO₂ could improve capillary regression via the change of pro- and anti-angiogenesis factors, which might be induced by an increase in blood flow.

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Browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes

Abstract

Mammalian adipose tissue is traditionally categorized into white and brown relating to their function and morphology: while white serves as an energy storage, brown adipose tissue acts as the heat generator maintaining the core body temperature. The most recently identified type of fat, beige adipocyte tissue, resembles brown fat by morphology and function but is developmentally more related to white. The synthesis of beige fat, so-called browning of white fat, has developed into a topical issue in diabetes and metabolism research. This is due to its favorable effect on whole-body energy metabolism and the fact that it can be recruited during adult life. Indeed, brown and beige adipose tissues have been demonstrated to play a role in glucose homeostasis, insulin sensitivity, and lipid metabolism—all factors related to pathogenesis of type 2 diabetes. Many agents capable of initiating browning have been identified so far and tested widely in humans and animal models including in vitro and in vivo experiments. Interestingly, several agents demonstrated to have browning activity are in fact secreted as adipokines from brown and beige fat tissue, suggesting a physiological relevance both in beige adipocyte recruitment processes and in maintenance of metabolic homeostasis. The newest findings on agents driving beige fat recruitment, their mechanisms, and implications on type 2 diabetes are discussed in this review.

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1 simple question to increase audience participation

Tackling the difficult challenge of encouraging participation by asking this simple question and waiting for a response

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Predictors of early recurrence after strictureplasty for Crohn’s disease of the small bowel during the years of biologics

The identification of patients prone to early recurrence of Crohn's disease at the site of a strictureplasty is fundamental in the clinical practice.

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Predictors of early recurrence after strictureplasty for Crohn’s disease of the small bowel during the years of biologics

The identification of patients prone to early recurrence of Crohn's disease at the site of a strictureplasty is fundamental in the clinical practice.

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Surgical Risk Stratification Based on Preoperative Risk Factors in Adult Spinal Deformity

Corrective surgery for adult spinal deformity (ASD) improves health-related quality of life but has high complication rates. Predicting a patient's risk of perioperative and late postoperative complications is difficult, although several potential risk factors have been reported. Purpose: To establish an accurate, ASD-specific model for predicting the risk of postoperative complications, based on baseline demographic, radiographic, and surgical invasiveness data in a retrospective case series.

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Assessment of Postoperative Outcomes in Spinal Epidural Abscess Following Surgical Decompression

A spinal epidural abscess (SEA) is a serious condition that may be managed with antibiotics alone or with decompressive surgery combined with antibiotics.

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Increased Emg Intermuscular Coherence and Reduced Signal Complexity in Parkinson’s Disease

The severity of the symptoms of Parkinson's disease (PD) are currently clinically evaluated using subjective scores such as the Movement Disorders Society Unified-Parkinson's-Disease-Rating-Scale (MDS-UPDRS) (Goetz et al., 2008). The semi-quantitative score, MDS-UPDRS III, provides a macro view of motor control without characterising specific patient kinematics. There is a recognised need for more quantitative measures to evaluate motor symptoms in PD which can provide insights into changes in neural control and provide an objective biomarker for diagnosis.

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Changes in event-related potentials during dual task walking in aging and Parkinson's disease

It has been theorized that walking in everyday life conditions requires higher cognitive processes that utilizes a complex neural network that incorporates cognitive and motor information (Woollacott and Shumway-Cook, 2002; Yogev-Seligmann et al., 2008). Most evidence supporting this notion relies on behavioral studies stemming from dual-task paradigms during walking to increase cognitive demands. These studies show that adding a simultaneous task to walking taxes executive function and attention and leads to changes in gait performance (Hausdorff et al., 2008; Yogev-Seligmann et al., 2008).

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Exploratory structural equation modeling for event‐related potential data—An all‐in‐one approach?

Abstract

ERP data are characterized by high dimensionality and a mixture of constituting signals and are thus challenging for researchers to analyze. To address these challenges, exploratory factor analysis (EFA) has been used to provide estimates of the unobserved factors and to use these estimates for further statistical analyses (e.g., analyses of group effects). However, the EFA approach is prone to biases due to assigning individual factor scores to each observation as an intermediate step and does not properly consider participants, electrodes, and groups/conditions as differentiable sources of factor variance, with the consequence that factor correlations are inaccurately estimated. Here, we suggest exploratory structural equation modeling (ESEM) as a potential approach to address these limitations. ESEM may handle the complexity of ERP data more appropriately because multiple sources of variance can be formally taken into consideration. We demonstrate the application of ESEM to ERP data (in comparison with EFA) with an illustrative example and report the results of a small simulation study in which ESEM clearly outperformed EFA with respect to accurate estimation of the population factor loadings, population factor correlations, and group differences. We discuss how robust statistical inference can be conducted within the ESEM approach. We conclude that ESEM naturally extends the current EFA approach for ERP data and that it can provide a coherent and flexible analysis framework for all kinds of ERP research questions.

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Table of Contents, Volume 176A, Number 11, November 2018

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In This Issue

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Cover Image, Volume 176A, Number 11, November 2018

The cover image is based on the Research Article First data from a parent‐reported registry of 81 individuals with Coffin–Siris syndrome: Natural history and management recommendations by Elizabeth A. Mannino et al., DOI: 10.1002/ajmg.a.40471.

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New Pachygyria Syndrome Linked to Actin Regulation Identified: When mutated, CTNNA2 leads to a new form of pachygyria that has a diffuse anterior‐posterior gradient with cerebellar hypoplasia, thinning corpus callosum, and absent anterior commissure

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Opitz Award Winner Defines Down Syndrome in Diverse Populations: Research will help clinicians identify patients with Down syndrome in non‐European populations

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Publication schedule for 2018

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The KV7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K+ channel currents

Key Points Summary

K_V7 channels are a family of voltage‐dependent K⁺ channels expressed in many cell types, which open in response to membrane depolarization to regulate cell excitability. Drugs that target K_V7 channels are used clinically to treat epilepsy. Interestingly, these drugs also cause urinary retention, but it was unclear how. In this study, we focused on two possible mechanisms by which retigabine could cause urinary retention: by decreasing smooth muscle excitability, or by decreasing sensory nerve outflow. Urinary bladder smooth muscle had no measurable K_V7 channel currents. However, the K_V7 channel agonist retigabine nearly abolished sensory nerve outflow from the urinary bladder during bladder filling. We conclude that K_V7 channel activation likely affects urinary bladder function by blocking afferent nerve outflow to the brain, which is key to sensing bladder fullness.

Abstract

K_V7 channels are voltage‐dependent K⁺ channels that open in response to membrane depolarization to regulate cell excitability. K_V7 activators, such as retigabine, were used to treat epilepsy but caused urinary retention. Using electrophysiological recordings from freshly isolated mouse urinary bladder smooth muscle (UBSM) cells, isometric contractility of bladder strips, and ex vivo measurements of bladder afferent activity, we explored the role of K_V7 channels as regulators of murine urinary bladder function. The K_V7 activator retigabine (10 μM) had no effect on voltage‐dependent K⁺ currents or resting membrane potential of UBSM cells, suggesting that these cells lacked retigabine‐sensitive K_V7 channels. The K_V7 inhibitor XE‐991 (10 μM) inhibited UBSM K⁺ currents; the properties of these currents, however, were typical of K_V2 channels and not K_V7 channels. Retigabine inhibited voltage‐dependent Ca²⁺ channel (VDCC) currents and reduced steady‐state contractions to 60 mM KCl in bladder strips, suggesting that reduction in VDCC current was sufficient to directly affect UBSM function. To determine if retigabine altered ex vivo bladder sensory outflow, we measured afferent activity during simulated transient contractions (TCs) of the bladder wall. Simulated TCs caused bursts of afferent activity that were nearly abolished by retigabine. The effects of retigabine were blocked by co‐incubation with XE‐991, suggesting specific activation of K_V7 channels on afferent nerves. These results indicate that retigabine primarily affects urinary bladder function by inhibiting TC generation and afferent nerve activity, which are key to sensing bladder fullness. Any direct inhibition of UBSM contractility is likely non‐specific effects on VDCCs and K_V2 channels.

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Impaired pressure natriuresis and non‐dipping blood pressure in Rats with early type 1 diabetes mellitus

Key points summary

Type 1 diabetes mellitus increases cardiovascular risk: hypertension amplifies this risk. Pressure natriuresis regulates long‐term blood pressure. We induced type 1 diabetes in rats by streptozotocin injection and after three weeks demonstrated a substantial impairment of pressure natriuresis: acute increases in blood pressure did not increase renal medullary blood flow, and tubular sodium reabsorption was not downregulated. Proximal tubule sodium reabsorption, measured by lithium clearance, was unaffected. Insulin reduced blood glucose in diabetic rats, and rescued the pressure natriuresis response without influencing lithium clearance. However, insulin did not restore medullary blood flow. On radiotelemetry, diastolic blood pressure was increased in diabetic rats, and its diurnal variation was reduced. Increases in medullary blood flow and decreases in distal tubule sodium reabsorption that offset acute rises in BP are impaired in early type 1 diabetes. Their impairment could be a target for preventing hypertension in type 1 diabetes.

Abstract

Type 1 diabetes mellitus (T1DM) substantially increases cardiovascular risk, and hypertension amplifies this risk. Blood pressure (BP) and body sodium homeostasis are linked. T1DM patients have increased total exchangeable sodium, correlating directly with BP. Pressure natriuresis is an important physiological regulator of BP. We hypothesised that pressure natriuresis would be impaired, and BP increased, in the early phase of T1DM. Male Sprague‐Dawley rats were injected with streptozotocin (30‐45 mg/kg) or citrate vehicle. After three weeks, pressure natriuresis was induced by serial arterial ligation. In non‐diabetic controls, this increased fractional excretion of sodium from ∼1% to ∼25% of the filtered load (P<0.01); in T1DM rats, the response was significantly blunted, peaking at only ∼3% (P<0.01). Mechanistically, normal lithium clearance suggested that distal tubular sodium reabsorption was not downregulated with increased BP in T1DM rats. The pressure‐dependence of renal medullary perfusion, considered a key factor in the integrated response, was abolished. Insulin therapy rescued the natriuretic response in diabetic rats, restoring normal downregulation of tubular sodium reabsorption when BP was increased. However, the pressure‐dependence of medullary perfusion was not restored, suggesting persistent vascular dysfunction despite glycaemic control. On radiotelemetry, T1DM did not affect systolic BP, but mean diastolic BP was ∼5 mmHg higher than in non‐diabetic controls (P<0.01), and normal diurnal variation was reduced. In conclusion, functional impairment of renal sodium and BP homeostasis is an early manifestation of T1DM, preceding hypertension and nephropathy. Early intervention to restore pressure natriuresis in T1DM may complement reductions in cardiovascular risk achieved with glycaemic control.

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Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Key Points

Wild type mice as well as mice with hepatocyte‐specific or whole‐body deletions of perilipin‐2 (Plin2) were used to define hepatocyte and extra‐hepatocyte effects of altered cellular lipid storage on obesity and non‐alcoholic fatty liver disease (NAFLD) pathophysiology in a western‐diet (WD) model of these disorders. Extra‐hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation, and glucose clearance abnormalities in WD‐fed mice. Hepatocyte and extra‐hepatic actions of Plin2 mediate fatty liver formation in WD‐fed mice through distinct mechanisms. Hepatocyte‐specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice.

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is an obesity and insulin resistance related metabolic disorder with progressive pathology. Perilipin‐2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate hepatocyte‐specific and extra‐hepatocyte Plin2 mechanisms regulating the effects of obesity and insulin resistance on NAFLD pathophysiology in mice fed an obesogenic western‐style diet (WD). Total Plin2 deletion (Plin2‐Null) fully protected WD‐fed mice from obesity, insulin resistance, adipose inflammation, steatohepatitis (NASH) and liver fibrosis found in WT animals. Hepatocyte specific Plin2 deletion (Plin2‐HepKO) largely protected against NASH and fibrosis and partially protected from steatosis in WD‐fed animals, but it did not protect against obesity, insulin resistance, or adipose inflammation. Significantly, total or hepatocyte specific Plin2 deletion impaired WD‐induced monocyte recruitment and pro‐inflammatory macrophage polarization found in livers of WT mice. Analyses of the molecular and cellular processes mediating steatosis, inflammation, and fibrosis identified differences in total and hepatocyte‐specific actions of Plin2 on the mechanisms promoting NAFLD pathophysiology. Our results demonstrate that hepatocyte‐specific actions of Plin2 are central to the initiation and pathological progression of NAFLD in obese and insulin resistant mice through effects on immune cell recruitment and fibrogenesis. Conversely, extra‐hepatocyte Plin2 actions promote NAFLD pathophysiology through effects on obesity, inflammation and insulin resistance. Our findings provide new insight into hepatocyte and extra‐hepatocyte mechanisms underlying NAFLD development and progression.

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Breaking the intergenerational cycle of obesity with SIRT1

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MRI measurement of blood‐brain barrier leakage: filling the gaps

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Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability

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MicroRNA Single Nucleotide Polymorphisms and Diabetes Mellitus: A Comprehensive Review

Diabetes mellitus (DM) has become the third major chronic non‐communicable disease affecting global public health, following cancer and cardiovascular and cerebrovascular diseases. Although previous studies have found a correlation between microRNA (miRNA) and the development of DM, thus far, most reviews have focused on the studies describing the changes in miRNA expression profiles and the mechanisms by which miRNAs‐induce DM. However, reviews summarizing the effect of miRNA single nucleotide polymorphisms (SNP) on the developmental stages of DM and its complications are still needed. Studies on the variation of miRNAs will not only help to further understand the role that genetic factors play in DM, but will also have important implications for treatment and disease prognosis.

This article is protected by copyright. All rights reserved.

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Preparing to migrate: expression of androgen signaling molecules and insulin-like growth factor-1 in skeletal muscles of Gambel’s white-crowned sparrows

Abstract

Migratory birds, including Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii), exhibit profound modifications of skeletal muscles prior to migration, notably hypertrophy of the pectoralis muscle required for powered flight. Muscle growth may be influenced by anabolic effects of androgens; however, prior to spring departure, circulating androgens are low in sparrows. A seasonal increase in local androgen signaling may occur within muscle to promote remodeling. We measured morphological parameters, plasma and tissue levels of testosterone, as well as mRNA expression levels of androgen receptor, 5α-reductase (converts testosterone to 5α-dihydrotestosterone), and the androgen-dependent myotrophic factor insulin-like growth factor-1. We studied the pectoralis muscle as well as the gastrocnemius (leg) muscle of male sparrows across three stages on the wintering grounds: winter (February), pre-nuptial molt (March), and pre-departure (April). Testosterone levels were low, but detectable, in plasma and muscles at all three stages. Androgen receptor mRNA and 5α-reductase Type 1 mRNA increased at pre-departure, but did so in both muscles. Notably, mRNA levels of insulin-like growth factor-1, an androgen-dependent gene critical for muscle remodeling, increased at pre-departure in the pectoralis but decreased in the gastrocnemius. Taken together, these data suggest a site-specific molecular basis for muscle remodeling that may serve to enable long-distance flight.

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Investigation of Hanwoo-specific structural variations using whole-genome sequencing data

Abstract

Background

The total length of the cattle genome is approximately ~ 3 billion base pairs. About half of the bovine genome (46.5%) is composed of transposable elements (TEs). The TEs could be a major source of genomic structural variations (SVs) between cattle breeds. These SVs have led to genomic fluidity and rearrangements between interspecies.

Objective

TE-mediated insertion and deletion events could have a strong influence on the bovine genome. This study aimed to investigate TE-mediated deletion events that are common to 12 Hanwoo genome resequencing data.

Results

We compared 12 Hanwoo genome resequencing data with the cattle reference genome (Bos taurus_UMD_3.1.1) and six other open source data (2 Jersey, 2 Holstein, 2 Angus). By using BreakDancer program, the common SVs to the 12 Hanwoo genomes were detected. A total of 299 Hanwoo-specific SV candidates were detected. Among them, 56 Hanwoo-specific TE-mediated deletion candidate loci were validated by PCR and Sanger sequencing. Finally, we identified one locus, DEL_96, which is an authentic Hanwoo-specific deletion. The DEL_96 event occurred by nonallelic homologous end-joining between LINE (BovB) and unique sequence with 1 bp microhomology. The 370 bp deletion event appeared to be only in the Hanwoo individuals after the divergence of Hanwoo and Holstein lineages.

Conclusion

Our study showed that one of the SVs, TE-mediated deletion, could be utilized as a molecular maker to distinguish between Hanwoo and Holstein.

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Seasonal evolution of 7,10Be and 22Na in the near surface atmosphere of Cáceres (Spain)

Publication date: February 2019

Source: Journal of Environmental Radioactivity, Volume 197

Author(s): A. Rodríguez-Perulero, A. Baeza, J. Guillén

Abstract

Cosmogenic radionuclides provide information about air masses exchanges between stratosphere and troposphere. The ⁷Be concentration in aerosols usually shows a seasonal variability, depending also of the climatic conditions. There are, however, fewer data available of the behavior of other cosmogenic radionuclides, such as ¹⁰Be and ²²Na. In this work about 7 years of aerosols collected in Cáceres (Spain) were analyzed. The ⁷Be concentration was higher than ²²Na and ¹⁰Be, being the ²²Na/⁷Be and ¹⁰Be/⁷Be ratios (1.16 ± 0.02)·10⁻⁴ and (1.5 ± 0.3)·10⁻⁴ respectively. For the ²²Na/⁷Be, a seasonal variation was observed, being higher in spring/summer. Seasonal variation of ⁷Be and ²²Na were explained using a model taking into account local values of the solar radiation, rainfall and dry deposition. The effective residence time for ⁷Be and ²²Na were (9.9 ± 1.0) and (11.3 ± 1.4) d respectively. Both ⁷Be and ²²Na seemed to decrease with increasing number of sunspots, although it was not statistically significant probably due to the low solar activity reported in the analyzed period.

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Measurement of terrestrial radiation level in a neotectonic fault system in Trinidad

Publication date: February 2019

Source: Journal of Environmental Radioactivity, Volume 197

Author(s): K.S. Banerjee, A. Baijoo

Abstract

Present study area, which is located in the Central Range Fault (CRF) in the island of Trinidad, can provide solution to that problem as this strike-slip fault system is reported to be active in present time (during Holocene, most current geological epoch) with a movement of geodetic rate of 12 ± 3 mm/yr. Most recent work, with improved GPS time series analysis indicated that as creeping fault rather than locked fault. Moreover, the selected fault system is accompanied by mud volcanoes, which can amplify the level of radiation activity by slight but significant anomalies as described by some researchers from other areas. Furthermore, being one of the first environmental radiation study in the Caribbean Islands, this study is significant. With the aim to achieve a continuous monitoring of radiological data to assess the activity along CRF for possible earthquake forecasting, objectives of this preliminary investigation are to delineate CRFZ using radiation survey and to investigate the potential of using this survey to detect tectonic activities in this zone. As a pilot study, radiation measurements were carried out with the help of a portable Geiger Muller counter in 52 locations along the 25 km long section of CRF between Naved Dam and Pointe-a-Pierre. Radiation measurements were taken both at 1 m level above the surface and at nearly 1 m below the ground. Results from this pilot study showed that lithology was not the lone contributor to terrestrial radiation levels, as CRFZ and associated fissure plane have good control also (∼3–5 times higher than the average background level). Although present study was not able to indicate the possibility of earthquakes in recent times (as previously stated), however, elevated radiation values in the vicinity of CRF, associated fissures (possibly interconnected fractures) and active mud volcanoes indicate possible activity in the study area. However, detail and periodic radiological studies are required before concluding that CRF is a creep fault rather than a locked fault.

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Humeral anatomy of the KNM-ER 47000 upper limb skeleton from Ileret, Kenya: Implications for taxonomic identification

Publication date: January 2019

Source: Journal of Human Evolution, Volume 126

Author(s): Michael R. Lague, Habiba Chirchir, David J. Green, Emma Mbua, John W.K. Harris, David R. Braun, Nicole L. Griffin, Brian G. Richmond

Abstract

KNM-ER 47000 is a fossil hominin upper limb skeleton from the Koobi Fora Formation, Kenya (FwJj14E, Area 1A) that includes portions of the scapula, humerus, ulna, and hand. Dated to ∼1.52 Ma, the skeleton could potentially belong to one of multiple hominin species that have been documented in the Turkana Basin during this time, including Homo habilis, Homo erectus, and Paranthropus boisei. Although the skeleton lacks associated craniodental material, the partial humerus (described here) preserves anatomical regions (i.e., distal diaphysis, elbow joint) that are informative for taxonomic identification among early Pleistocene hominins. In this study, we analyze distal diaphyseal morphology and the shape of the elbow region to determine whether KNM-ER 47000 can be confidently attributed to a particular species. The morphology of the KNM-ER 47000 humerus (designated KNM-ER 47000B) is compared to that of other early Pleistocene hominin fossil humeri via the application of multivariate ordination techniques to both two-dimensional landmark data (diaphysis) and scale-free linear shape data (elbow). Distance metrics reflecting shape dissimilarity between KNM-ER 47000B and other fossils (and species average shapes) are assessed in the context of intraspecific variation within modern hominid species (Homo sapiens, Pan troglodytes, Gorilla gorilla, Pongo pygmaeus). Our comparative analyses strongly support attribution of KNM-ER 47000 to P. boisei. Compared to four other partial skeletons that have (justifiably or not) been attributed to P. boisei, KNM-ER 47000 provides the most complete picture of upper limb anatomy in a single individual. The taxonomic identification of KNM-ER 47000 makes the skeleton an important resource for testing future hypotheses related to P. boisei upper limb function and the taxonomy of isolated early Pleistocene hominin remains.

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Diagnostic sensitivity of electrophysiology and ultrasonography in ulnar neuropathies of different severity

Publication date: Available online 7 December 2018

Source: Clinical Neurophysiology

Author(s): Luciana Pelosi, Eoin Mulroy

Abstract

Objective

To assess the diagnostic performance of electrophysiology and nerve ultrasound in ulnar neuropathies of varying clinical severity in 135 consecutive patients

Methods

Clinical severity of ulnar neuropathy was graded on a 4 point scale from very mild (symptoms only) to severe (marked atrophy of intrinsic hand muscles). Sensitivity and localization ability of electrophysiology and nerve ultrasound were assessed for each point of the scale.

Results

Ultrasound had higher sensitivity than electrophysiology in clinically very mild (20 and 3% for ultrasound and electrophysiology, respectively) and mild (62 and 47% for ultrasound and electrophysiology, respectively) neuropathies, had greater localizing ability in axonal ulnar neuropathies, and identified nerve hypermobility.

Ultrasound nerve cross-sectional area had strong positive correlation with both clinical and electrophysiological severity scores, but with significant overlap across the severity groups.

Conclusion

The diagnostic work-up of ulnar neuropathies was improved by using both electrophysiology and ultrasound at all levels of clinical severity. Ultrasound increased the diagnostic yield in very mild and mild neuropathies, localized all the ulnar neuropathies with abnormal non-localizing electrophysiology and identified nerve hypermobility.

Significance

This is the first detailed analysis of the diagnostic performance of electrophysiology and ultrasound in ulnar neuropathies of varying severity

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Increased Emg Intermuscular Coherence and Reduced Signal Complexity in Parkinson’s Disease

Publication date: Available online 8 December 2018

Source: Clinical Neurophysiology

Author(s): MW. Flood, BR. Jensen, AS. Malling, MM. Lowery

Abstract

Objectives

To investigate differences in surface electromyography (EMG) features in individuals with idiopathic Parkinson's disease (PD) and aged-matched controls.

Methods

Surface EMG was recorded during isometric leg extension in PD patients prior to, and after undergoing a locomotor training programme, and in aged-matched controls. Differences in EMG structure were quantified using determinism (%DET), sample entropy (SampEn) and intermuscular coherence.

Results

%DET was significantly higher, and SampEn significantly lower, in PD patients. Intermuscular coherence was also significantly higher in the PD group in theta, alpha and beta frequency bands. %DET increased and SampEn decreased with increasing Movement-Disorder-Society UPDRS scores, while theta band coherence was significantly correlated with total MDS-UPDRS scores and torque variance. Neither %DET, SampEn nor intermuscular coherence changed in response to training.

Conclusions

The differences observed are consistent with increased synchrony among motor units within and across leg muscles in PD. Differences between EMG signals recorded from the PD and control groups persisted post-therapy, after improvements in walking capacity occurred.

Significance

These results provide insight into changes in motoneuron activity in PD, demonstrate increased beta band intramuscular coherence in PD for the first time, and support the development of quantitative biomarkers for PD based on advanced surface EMG features.

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Changes in event-related potentials during dual task walking in aging and Parkinson's disease

Publication date: Available online 8 December 2018

Source: Clinical Neurophysiology

Author(s): Inbal Maidan, Firas Fahoum, Shiran Shustak, Eran Gazit, Dmitry Patashov, Dmitry Tchertov, Nir Giladi, Jeffrey M Hausdorff, Anat Mirelman

Abstract

Objective

To investigate EEG changes during an auditory odd-ball task while walking (dual-task) in young adults, older adults, and patients with Parkinson's disease.

Methods

11 young adults, 10 older adults, and 10 patients with Parkinson's disease (PD) performed an auditory oddball task during standing and walking on a treadmill. The amplitude and latency of P300 were compared between groups and within conditions using linear mix model analysis. Gait was evaluated using wearable sensors and cognition was assessed using the Color Trail Test.

Results

P300 latency became longer during walking in all groups (p=0.005). During walking, older adults (p=0.005) and patients with PD (p=0.001) showed prolonged P300 latency compared to young adults. Significant task by group interaction was found in P300 amplitude (p=0.008). Patients with PD demonstrated reduced P300 amplitude during walking compared to standing (p=0.023). Among all subjects, better motor and cognitive performance correlated with shorter P300 latency (r=0.457, p=0.014 and r=0.431, p=0.040, respectively).

Conclusions

These findings provide direct evidence of the physiological recruitment of attentional networks during walking and their impact by ageing and disease.

Significance

This study is the first to report on changes in P300 latency and amplitude during dual-task oddball walking in older adults and patients with PD.

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Cognitive and motor event-related potentials in Tourette syndrome and tic disorders: a systematic review

Publication date: Available online 7 December 2018

Source: Clinical Neurophysiology

Author(s): Simon Morand-Beaulieu, Marc E. Lavoie

Abstract

Objectives

Tourette syndrome (TS) patients face various cognitive and motor impairments. Event-related potentials (ERP) constitute an effective way to investigate the neural correlates of those functional impairments. Various components have been assessed among TS patients, with a wide variety of paradigms. This systematic review aimed to evaluate the portrait of ERP components in TS patients, and to understand the factors leading to discrepancies across studies.

Methods

A literature search was performed in Embase, PsycINFO, Pubmed, and Web of Science, to identify studies that conducted ERP experiments among TS patients. Of the 372 unique records identified, 47 met inclusion criteria and were included in our systematic review.

Results

Various ERP particularities were reported among included studies. Many discrepancies exist, but impairments in motor-related potentials and contingent negative variation seem constant across studies. Divergent findings point toward a possibly reduced P3b during oddball tasks.

Conclusions

ERPs offer an insightful investigation into the cognitive and motor functions of TS patients. Future studies should always control for confounding factors such as comorbidity, age, or medication status.

Significance

This is the first systematic review of ERP in TS patients. Motor-related and slow cortical potentials could constitute electrophysiological markers of TS.

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De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment

Abstract

ATP2B2 encodes the PMCA2 Ca²⁺ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca²⁺ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3–6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.

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Identification of tissue-specific tumor biomarker using different optimization algorithms

Abstract

Background

Identification of differentially expressed genes, i.e., genes whose transcript abundance level differs across different biological or physiological conditions, was indeed a challenging task. However, the inception of transcriptome sequencing (RNA-seq) technology revolutionized the simultaneous measurement of the transcript abundance levels for thousands of genes.

Objective

In this paper, such next-generation sequencing (NGS) data is used to identify biomarker signatures for several of the most common cancer types (bladder, colon, kidney, brain, liver, lung, prostate, skin, and thyroid)

Methods

Here, the problem is mapped into the comparison of optimization algorithms for selecting a set of genes that lead to the highest classification accuracy of a two-class classification task between healthy and tumor samples. As the optimization algorithms Artificial Bee Colony (ABC), Ant Colony Optimization, Differential Evolution, and Particle Swarm Optimization are chosen for this experiment. A standard statistical method called DESeq2 is used to select differentially expressed genes before being feed to the optimization algorithms. Classification of healthy and tumor samples is done by support vector machine

Results

Cancer-specific validation yields remarkably good results in terms of accuracy. Highest classification accuracy is achieved by the ABC algorithm for Brain lower grade glioma data is 99.10%. This validation is well supported by a statistical test, gene ontology enrichment analysis, and KEGG pathway enrichment analysis for each cancer biomarker signature

Conclusion

The current study identified robust genes as biomarker signatures and these identified biomarkers might be helpful to accurately identify tumors of unknown origin

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