Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia.

OBJECTIVE: To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia. MATERIALS AND METHODS: A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR. RESULTS: Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN. CONCLUSION: The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery. WHAT DOES THIS STUDY ADDS TO THE CLINICAL WORK: Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

Colorectal and bladder prokinetic activity of [Lys5, MeLeu9, Nle10]-NKA(4-10) after intranasal or sublingual delivery in dogs.

The feasibility of eliciting defecation and urination after intranasal (IN) or sublingual (SL) delivery of a small peptide NK2 receptor agonist, [Lys5, MeLeu9, Nle10]-NKA(4-10), was examined using prototype formulations in dogs. In anesthetized animals, administration of 100 or 300 µg/kg IN or 2.0-6.7 mg/kg SL increased colorectal peak pressure and area under the curve. Peak bladder pressure was also increased at the same doses, and this was accompanied by highly efficient voiding at normal physiological bladder pressure. The onset of these effects was rapid (≤2.5 min), and the primary contractions lasted ∼25 min, returning to baseline in <60 min. Slight hypotension lasting a few minutes and causing <10% change from baseline was detected after higher doses and was statistically significant after only 100 µg/kg IN. In conscious dogs, there was a dose-related increase in voiding responses and reduction in the latency to urinate and defecate after 300 and 1000 µg/kg IN; emesis was also observed at these doses. SL administration of 6.7 mg/kg induced urination within 10 min, but not defecation or emesis. These findings support the feasibility of developing a convenient dosage form of small peptide NK2 receptor agonists as on-demand defecation or urination therapies.

Phosphorylated tau in plasma could be a biomarker of lower motor neuron impairment in amyotrophic lateral sclerosis.

INTRODUCTION: Plasma levels of phosphorylated tau (P-tau181) have been recently reported to be increased in amyotrophic lateral sclerosis (ALS) and associated with lower motor neuron (LMN) impairment. PATIENTS AND METHODS: We quantified plasma P-tau181 (pP-tau181) in a cohort of 29 deeply phenotyped ALS patients using the new fully automated Lumipulse assay and analysed phenotype-biomarker correlations. RESULTS: pP-tau181 levels correlated positively with a clinical LMN score (r = 0.3803) and negatively, albeit not significantly, with a composite index of muscle strength (r = - 0.3416; p = 0.0811), but not with Penn Upper Motor Neuron (UMN) Score. Accordingly, pP-tau181 correlated with electromyographic indices of spinal active and chronic denervation (r = 0.4507 and r = 0.3864, respectively) but not with transcranial magnetic stimulation parameters of UMN dysfunction. pP-tau181 levels did not correlate with those in the cerebrospinal fluid (CSF), serum NFL, serum GFAP, CSF/serum albumin ratio, or estimated glomerular filtration rate, but correlated with plasma creatine kinase levels (r = 0.4661). Finally, while not being associated with neuropsychological phenotype, pP-tau181 correlated negatively with pH (r = - 0.5632) and positively with partial pressure of carbon dioxide (PaCO2; r = 0.7092), bicarbonate (sHCO3-; r = 0.6667) and base excess (r = 0.6611) on arterial blood gas analysis. DISCUSSION: pP-tau181 has potential as ALS biomarker and could be associated with LMN impairment. Its raised levels might reflect pathophysiological processes (tau hyperphosphorylation and/or release) occurring in the axons of LMNs distantly from the CNS and the CSF. pP-tau181 could also be associated with respiratory dysfunction.

Intermuscular coherence in amyotrophic lateral sclerosis: A preliminary assessment.

INTRODUCTION: Simple laboratory tests of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS) are not available. Intermuscular coherence has been shown to distinguish patients with primary lateral sclerosis, a pure upper motor neuron disorder, from normal subjects, suggesting it could be useful for assessing ALS. We aimed to determine whether intermuscular coherence can distinguish ALS patients from normal subjects. METHODS: We measured biceps brachii and brachioradialis activity using surface electromyography while subjects held the elbow at flexion and the forearm in semipronation. Intermuscular coherence was calculated at between 20 and 40 Hz in 15 ALS patients and 15 normal subjects. RESULTS: On average, intermuscular coherence was 3.8-fold greater in normal subjects than in ALS patients (P < 0.01), and it distinguished ALS patients from normal subjects with a sensitivity of 87% and specificity of 87%. CONCLUSION: Intermuscular coherence measurement is a rapid, painless method that may detect upper motor neuron dysfunction in ALS. Muscle Nerve 55: 862-868, 2017.

A neurophysiological approach to nerve transfer to restore upper limb function in cervical spinal cord injury.

A successful nerve transfer surgery can provide a wealth of benefits to a patient with cervical spinal cord injury. The process of surgical decision making ideally uses all pertinent information to produce the best functional outcome. Reliance on clinical examination and imaging studies alone can miss valuable information on the state of spinal cord health. In this regard, neurophysiological evaluation has the potential to effectively gauge the neurological status of even select pools of anterior horn cells and their axons to small nerve branches in question to determine the potential efficacy of their use in a transfer. If available preoperatively, knowledge gained from such an evaluation could significantly alter the reconstructive surgical plan and avoid poor results. The authors describe their institution's approach to the assessment of patients with cervical spinal cord injury who are being considered for nerve transfer surgery in both the acute and chronic setting and broadly review the neurophysiological techniques used.

Establishing reconstructive neurosurgery as a subspecialty.

Neurosurgery is experiencing the emergence of a new subspecialty focused on function restoration. New, evolving, and reappraised surgical procedures have provided an opportunity to restore function to many patients with previously undertreated disorders. Candidates for reconstruction were previously limited to those with peripheral nerve and brachial plexus injuries, but this has been expanded to include stroke, spinal cord injury, and a host of other paralyzing disorders affecting both upper and lower motor neurons. Similar to the recent evolution of the well-established subdisciplines of spinal and vascular neurosurgery, reconstructive neurosurgery requires the adaptation of techniques and skills that were not traditionally a part of neurosurgical training. Neurosurgeons-as the specialists who already manage this patient population and possess the requisite surgical skills to master the required techniques-have a unique opportunity to lead the development of this field. The full development of this subspecialty will lay the foundation for the subsequent addition of emerging treatments, such as neuroprosthetics and stem cell-based interventions. As such, reconstructive neurosurgery represents an important aspect of neurosurgical training that can ameliorate many of the deficits encountered in the traditional practice of neurosurgery.

Analysis of motor unit firing characteristics in patients with motor neuron diseases.

This study was designed to evaluate firing rate variability in patients with upper/lower motor neuron disorders. Twenty healthy subjects and 19 patients with motor neuron disorders participated in the study. Consecutive motor unit action potential pairs from extensor digitorum communis (EDC) muscle were recorded from each subject with trigger-delay line mode. Patients with motor neuron disorders (17.7 ± 10.8 ms) showed significantly higher mean time variability of interpotential interval value than healthy volunteers (10.3 ± 0.1 ms) (p < 0.001).

Mapping lower-limbs muscle vulnerability in patients with ALS: The role of upper and lower motor neurons.

BACKGROUND: Several studies have reported disproportionate wasting of the flexor muscles of the lower limbs (LL) compared to the extensors in patients with amyotrophic lateral sclerosis (ALS). However, these studies have involved small sample sizes (n ã€ˆ100), and their findings have been inconsistent. Thus, it remains uncertain whether a distinct pattern of LL muscle weakness is specific to ALS. AIMS: To investigate the muscle weakness pattern in the LL at the knee, ankle, and toes in a large cohort of ALS patients and evaluate the relationship between the pattern of muscle strength and the extent of upper (UMN) and lower (LMN) motoneuron impairment. MATERIAL AND METHODS: The strength of flexor and extensor muscle was evaluated in 1250 legs of newly diagnosed ALS patients at the knee, ankle, and foot toes. UMN and LMN burden were assessed using validated scores. Within-subjects ANOVA considering the type of muscle (flexor/extensor) and anatomical sites (knee/ankle/toes) and mixed-factorial ANOVA were conducted to explore the impact of UMN and LMN impairments on the muscle weakness pattern. RESULTS: Muscle strength showed a significant decline from proximal to distal regions. Indeed both flexor and extensor muscles at the knee outperformed those at the ankle and toes. Within each site, extensor muscles exhibited less strength than flexor, except at the knee. Patients with heightened UMN impairment showed a more marked difference between flexors and extensors within each site, with extensor muscles being more compromised at the ankle and toes. Higher LMN impairment corresponded to a more pronounced weakness in flexor muscles at the ankle and toes compared to those at the knee. CONCLUSIONS: The extensor muscle at the knee and the flexors at the foot and toes displayed relative resistance to ALS disease. UMN impairment amplified the differences between flexor and extensor muscles within each site, while LMN impairment demonstrated a clear distal-to-proximal vulnerability.

Cross-subject EEG-based emotion recognition through dynamic optimization of random forest with sparrow search algorithm.

The objective of EEG-based emotion recognition is to classify emotions by decoding signals, with potential applications in the fields of artificial intelligence and bioinformatics. Cross-subject emotion recognition is more difficult than intra-subject emotion recognition. The poor adaptability of classification model parameters is a significant factor of low accuracy in cross-subject emotion recognition. We propose a model of a dynamically optimized Random Forest based on the Sparrow Search Algorithm (SSA-RF). The decision trees number (DTN) and the leave minimum number (LMN) of the RF are dynamically optimized by the SSA. 12 features are used to construct feature combinations for selecting the optimal feature combination. DEAP and SEED datasets are employed for testing the performance of SSA-RF. The experimental results show that the accuracy of binary classification is 76.81% on DEAP, and the accuracy of triple classification is 75.96% on SEED based on SSA-RF, which are both higher than that of traditional RF. This study provides new insights for the development of cross-subject emotion recognition, and has significant theoretical value.

Complete and incomplete lower motor neuron facial palsy in post-COVID-19 mucormycosis.

Purpose: To study facial nerve palsy (FNP) in post-COVID-19-mucormycosis patients and its ocular complications, report different presentations of FNP in such patients, and propose its etiopathogenesis based on presentation and clinico-radiologic localization. Methods: A prospective cohort study was carried out in patients of post-COVID-19-mucormycosis who presented at our tertiary center, over a period of 3 months. Motor and sensory examination of the facial nerve was done to diagnose FNP and localize the lesion clinically. Slit-lamp examination was done for grading corneal involvement. MRI brain, orbit, and paranasal sinuses (PNS) with contrast were studied to find involvement along the facial nerve. It was assessed whether this site of lesion corresponded with clinical localization. Data were analyzed using the percentage of total cases and Fisher's test. Results: A total of 300 patients with post-COVID-19 mucormycosis were examined, of which 30 (10%) patients were found to have FNP. All were lower motor neuron (LMN) type and were associated with corneal complications. The most common site clinically was distal to the chorda tympani (66.66%) and radiologically was infratemporal (IT) fossa (63.4%). The clinical localization significantly correlated with the radiological findings (P = 0.012). Twenty percent of patients showed incomplete involvement of facial muscles. Conclusion: FNP was found to be of LMN type. The most common site of insult was IT fossa. There was a good clinico-radiological correspondence of lesions. Isolated lesions were also found along the peripheral nerve course, presenting as incomplete facial palsy. Recognition of FNP in post-COVID-19 mucormycosis, in all its variable forms, is important to manage corneal complications.

Neurophysiological differentiation of upper motor neuron damage in neurodegenerative disorders.

Objective: Using transcranial magnetic stimulation (TMS) to delineate upper motor neuron (UMN) signs of two neurodegenerative disorders: amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA). Methods: Medical records including clinical signs for UMN damage and TMS results were reviewed retrospectively. The UMN signs were classified into none, mild, and severe based on neurological examination of various reflexes. Then TMS-elicited motor evoked potentials (MEPs) were recorded from a hand and a leg muscle to calculate the central motor conduction time (CMCT), which represents fast, mono-synaptic conduction along the corticospinal tract. Relations between the UMN signs and CMCT were analysed for the two diseases. Results: Prevalence and severity of the UMN signs for ALS and MSA were comparable for both upper and lower limbs. However, abnormality in CMCT was found more frequently in ALS: CMCT abnormalities were found in upper limbs for 44% in ALS patients but only for 7% in MSA patients; CMCT abnormalities in lower limbs were 55% in ALS and 20% in MSA. Some ALS patients showed abnormal CMCT in limbs without UMN signs, which was not true for most MSA patients. Conclusions: The abnormalities of CMCT were different in ALS and MSA, even for those who clinically had similar UMN signs. Sometimes, CMCT can reveal UMN damage in the absence of clinical UMN signs. Differences presumably derive from selective degeneration of different fibres in the motor descending pathways. Longitudinal studies must be conducted to accumulate neuroimaging and pathological findings. Significance: CMCT can be useful to differentiate ALS and MSA.

Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry.

INTRODUCTION AND OBJECTIVES: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. METHODS: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. RESULTS: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001). CONCLUSIONS: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.

Testing the long-run neutrality and superneutrality of money in a developing country: Evidence from Iran.

This paper investigates the long-run money neutrality (LMN) and long-run money superneutrality (LMSN) hypothesis for both the industry sector and the entire Iranian economy by using the data of 1979-2018 and applying Fisher and Seater's (1993) ARIMA framework. Conventional unit root tests, including PP, ADF, and KPSS, are applied to determine the order of integration of variables; however, since the structural break in variables is not considered in these methods, Lee-Strazicich and Zivot-Andrews methods are also applied to take it into account. The findings of money neutrality investigation in the Iranian industry sector show that when the monetary base is the criterion, money neutrality is confirmed, but when liquidity and money volume are the criteria, money neutrality is rejected. Also, the neutrality of money is accepted considering all three monetary aggregates (M1, M2, and M3) in investigating the entire economy. It is not feasible to examine the superneutrality of money since unit root tests confirm that all the variables are I (1).•As there is more than one structural break in the time series of the study, applying the Lee-Strazicich unit root test has made the results more reliable.•Neutrality of money testing is not efficient in the case of cointegration between model variables. Thus, the Gregory-Hansen test, which investigates cointegration considering the structural break, is applied.•The results of this research can guide policy-makers.•Non-neutrality of money in the industrial sector shows the positive effect of monetary policy on this sector when considering the probability of destructive effects on other sectors.

20(S)-ginsenoside Rh2 as agent for the treatment of LMN-CRC via regulating epithelial-mesenchymal transition.

The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial-mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC.

Electrical stimulation and denervated muscles after spinal cord injury.

Spinal cord injury (SCI) population with injury below T10 or injury to the cauda equina region is characterized by denervated muscles, extensive muscle atrophy, infiltration of intramuscular fat and formation of fibrous tissue. These morphological changes may put individuals with SCI at higher risk for developing other diseases such as various cardiovascular diseases, diabetes, obesity and osteoporosis. Currently, there is no available rehabilitation intervention to rescue the muscles or restore muscle size in SCI individuals with lower motor neuron denervation. We, hereby, performed a review of the available evidence that supports the use of electrical stimulation in restoration of denervated muscle following SCI. Long pulse width stimulation (LPWS) technique is an upcoming method of stimulating denervated muscles. Our primary objective is to explore the best stimulation paradigms (stimulation parameters, stimulation technique and stimulation wave) to achieve restoration of the denervated muscle. Stimulation parameters, such as the pulse duration, need to be 100-1000 times longer than in innervated muscles to achieve desirable excitability and contraction. The use of electrical stimulation in animal and human models induces muscle hypertrophy. Findings in animal models indicate that electrical stimulation, with a combination of exercise and pharmacological interventions, have proven to be effective in improving various aspects like relative muscle weight, muscle cross sectional area, number of myelinated regenerated fibers, and restoring some level of muscle function. Human studies have shown similar outcomes, identifying the use of LPWS as an effective strategy in increasing muscle cross sectional area, the size of muscle fibers, and improving muscle function. Therefore, displaying promise is an effective future stimulation intervention. In summary, LPWS is a novel stimulation technique for denervated muscles in humans with SCI. Successful studies on LPWS of denervated muscles will help in translating this stimulation technique to the clinical level as a rehabilitation intervention after SCI.

Corrosion Resistance of Stainless Steels Intended to Come into Direct or Prolonged Contact with the Skin.

The biocompatibility of materials in contact with a living tissue becomes a puzzle in the overall picture of assessing the toxic effects of chemicals that come into contact with us. Allergic reactions to substances are a significant and growing health problem affecting large parts of the population in Europe. Wristwatches are objects worn in prolonged contact with the skin, being subject to localized corrosion, especially pitting and crevice types, in sulfide-chloride medium, and high wear in the bracelets joints. Watches of medium quality are usually made of stainless steels. The X2 CrNiMo 17-12-2 316L grade as well as X1 CrNiMo 20-25-5 Cu 1 or 904L are commonly used, having good resistance to generalized corrosion. The passive layer is nevertheless insufficient to ensure complete immunity in all cases of localized corrosion encountered during wear. For this reason, a high-corrosion-resistant steel: X1 CrNiMo 18-15-4 N 0.15 or 317LMN, from three different suppliers was evaluated. Metallographic characterization was carried out. The corrosion behavior evaluation was performed for the generalized corrosion, pitting and crevice corrosion and galvanic corrosion. Galvanic couples steel 317LMN-gold 18K alloy 3N and gold 18K 5M were used. The results of the generalized and pitting corrosion test indicated three basic groups. All of the 317LMNs were similar. The 316L variants tested noticeably worse. The 904Ls were difficult to discern, but certainly easier than the 316Ls and, possibly, at least comparable to the 317LMNs.

How Accurately Can We Measure the Reconnection Rate E M for the MMS Diffusion Region Event of 11 July 2017?

We investigate the accuracy with which the reconnection electric field E M can be determined from in situ plasma data. We study the magnetotail electron diffusion region observed by National Aeronautics and Space Administration's Magnetospheric Multiscale (MMS) on 11 July 2017 at 22:34 UT and focus on the very large errors in E M that result from errors in an L M N boundary normal coordinate system. We determine several L M N coordinates for this MMS event using several different methods. We use these M axes to estimate E M. We find some consensus that the reconnection rate was roughly E M = 3.2 ± 0.6 mV/m, which corresponds to a normalized reconnection rate of 0.18 ± 0.035. Minimum variance analysis of the electron velocity (MVA-v e), MVA of E, minimization of Faraday residue, and an adjusted version of the maximum directional derivative of the magnetic field (MDD-B) technique all produce reasonably similar coordinate axes. We use virtual MMS data from a particle-in-cell simulation of this event to estimate the errors in the coordinate axes and reconnection rate associated with MVA-v e and MDD-B. The L and M directions are most reliably determined by MVA-v e when the spacecraft observes a clear electron jet reversal. When the magnetic field data have errors as small as 0.5% of the background field strength, the M direction obtained by MDD-B technique may be off by as much as 35°. The normal direction is most accurately obtained by MDD-B. Overall, we find that these techniques were able to identify E M from the virtual data within error bars ≥20%.

Transcription Factor-Mediated Differentiation of Human iPSCs into Neurons.

Accurate modeling of human neuronal cell biology has been a long-standing challenge. However, methods to differentiate human induced pluripotent stem cells (iPSCs) to neurons have recently provided experimentally tractable cell models. Numerous methods that use small molecules to direct iPSCs into neuronal lineages have arisen in recent years. Unfortunately, these methods entail numerous challenges, including poor efficiency, variable cell type heterogeneity, and lengthy, expensive differentiation procedures. We recently developed a new method to generate stable transgenic lines of human iPSCs with doxycycline-inducible transcription factors at safe-harbor loci. Using a simple two-step protocol, these lines can be inducibly differentiated into either cortical (i3 Neurons) or lower motor neurons (i3 LMN) in a rapid, efficient, and scalable manner (Wang et al., 2017). In this manuscript, we describe a set of protocols to assist investigators in the culture and genetic engineering of iPSC lines to enable transcription factor-mediated differentiation of iPSCs into i3 Neurons or i3 LMNs, and we present neuronal culture conditions for various experimental applications. © 2018 by John Wiley & Sons, Inc.

Facial Nerve Paralysis in Acute Suppurative Otitis Media-Management.

Facial paralysis is a rare complication of acute suppurative otitis media which requires early detection and appropriate care. We hereby report a case which we managed conservatively with good outcome. Following our experience and review of literature on the subject, antibiotic therapy and corticosteroid therapy, with or without myringotomy were found to be the first-line procedures. Surgery should be employed in case of acute or coalescent mastoiditis, suppurative complications and lack of clinical regression.