Comparison of risk scores for predicting intravenous immunoglobulin resistance in Taiwanese patients with Kawasaki disease.

BACKGROUND/PURPOSE: Kawasaki disease (KD) is the most common type of acquired heart disease in children, and intravenous immunoglobulin (IVIG) therapy is the preferred treatment. Several risk scoring systems have been developed to predict IVIG resistance, which is important in KD management, including the Kobayashi, Egami, and Formosa scores. We evaluated the performance of these scoring systems with a KD patient cohort from Taiwan. METHODS: We retrospectively analyzed the medical records of all KD patients admitted to our institution from 2012 to 2017. We compared the characteristics of IVIG-resistant and non-resistant patients and evaluated the predictive ability of the scoring systems for IVIG resistance. RESULTS: We included 84 patients, with 73 receiving IVIG therapy. Eight patients were unresponsive to the first IVIG course. Compared to those with good response to therapy or spontaneous improvement, IVIG-resistant patients had a higher C-reactive protein level (16.1 mg/dL vs. 8.6 mg/dL, p < 0.001), higher percentage of segmented leukocytes (75.7% vs. 61.7%, p = 0.008), and lower albumin level (2.98 mg/dL vs. 3.78 mg/dL, p = 0.001). In determining IVIG resistance, the sensitivity and specificity varied among scoring systems (Kobayashi, 37.5% and 86.8%; Egami, 37.5% and 84.2%; and Formosa, 87.5% and 73.7%, respectively). The positive and negative predictive values of the Formosa score were 25.9% and 98.2%, respectively. CONCLUSION: The Formosa score had the highest sensitivity in determining IVIG resistance. Although the positive predictive value was low, the negative predictive value could reach 98.2%. The Formosa score was superior to other scoring systems in predicting IVIG resistance in Taiwanese KD patients.

The quantity-effect relationship and physiological mechanisms of different acupuncture manipulations on posterior circulation ischemia with vertigo: study protocol for a randomized controlled trial.

BACKGROUND: Recent experiments have demonstrated that different needling manipulations may induce variable effects via diverse physiological mechanisms. A previous study indicated that needling at Fengchi (GB 20) improved cerebral blood flow in patients with vertigo induced by posterior circulation ischemia (PCI). In this study, we aim to explore the quantity-effect relationship and the physiological mechanisms underlying different acupuncture manipulations in PCI patients with vertigo. METHODS/DESIGN: We propose a pragmatic randomized and controlled trial. All participants, outcome assessors, and statisticians will be blinded. A total of 144 eligible participants will be randomized into one of four treatment groups receiving acupuncture at Fengchi (GB 20) with different one-minute manipulation parameters. Group 1 will receive twirling at a frequency of 60 times per minute toward the contralateral outer canthus at a depth of 0.5 to 0.8 cun. Group 2 will receive twirling at a frequency of 60 times per minute toward the Adam's apple at a depth of 0.5 to 0.8 cun. Group 3 will receive twirling at a frequency of 120 times per minute toward the contralateral outer canthus at a depth of 0.5 to 0.8 cun. Group 4 will receive twirling at a frequency of120 times per minute toward the Adam's apple at a depth of 0.5 to 0.8 cun. Additional points will be added based on individualized pattern diagnoses. The participants will receive 14 acupuncture sessions over 3 to 4 weeks. The subjects will be assessed at two time points: baseline and post-treatment. The primary outcome measurements will include subjective measurements (Vertebrobasilar System Ischemic Neurological Impairment Scale, UCLA Dizziness Questionnaire, Activities of Daily Living Scale, and Psychological and Social Adaptation Scale) and objective measurements (Transcranial Doppler, carotid ultrasonography and changes in cerebral oxygenation) to reduce bias arising from the placebo effect. We will use metabolomics to investigate the mechanisms underlying the different manipulation parameters. DISCUSSION: This trial aims to explore the quantity-effect relationship between different acupuncture manipulations and their clinical effects. The results from this study may help explain the contradictory results found in acupuncture studies that practice different manipulations. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-RTRCC-12002675 (registered on 14 November 2012).

Usefulness of S100A12 as a prognostic biomarker for adverse events in patients with heart failure.

OBJECTIVES: S100A12 has been proposed as a novel pivotal factor in inflammation produced by granulocytes. The purpose of this study was to investigate the relationship between S100A12 and chronic heart failure (CHF). DESIGN AND METHODS: One hundred and seventy-seven patients with CHF and 66 subjects without CHF were included in this study. Plasma levels of S100A12 and high-sensitivity C-reactive protein (hs-CRP) were measured in all participants. After a follow-up period of 18months for CHF patients, major cardiovascular events (MCE), including cardiac death and rehospitalization for heart failure, were recorded. RESULTS: Plasma levels of S100A12 were significantly higher in CHF patients than in control subjects (P<0.001) and positively correlated with hs-CRP (r=0.316, P<0.001). S100A12 levels were also higher in MCE patients than in MCE-free patients. The occurrence of MCE increased with advancing plasma S100A12 levels by stratification according to quartiles (Q4 vs Q1, P=0.015). Cox proportional hazards regression analysis revealed that S100A12 was an independent risk factor for MCE in CHF patients (P=0.009). CONCLUSIONS: S100A12 is a potential biomarker of CHF that may provide important information regarding the prediction of MCE in patients with CHF.

Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the beta1 subunit.

In response to sustained depolarization or prolonged bursts of activity in spiking cells, sodium channels enter long-lived non-conducting states from which recovery at hyperpolarized potentials occurs over hundreds of milliseconds to seconds. The molecular basis for this slow inactivation remains unknown, although many functional domains of the channel have been implicated. Expression studies in Xenopus oocytes and mammalian cell lines have suggested a role for the accessory beta1 subunit in slow inactivation, but the effects have been variable. We examined the effects of the beta1 subunit on slow inactivation of skeletal muscle (NaV1.4) sodium channels expressed in HEK cells. Co-expression of the beta1 subunit impeded slow inactivation elicited by a 30-s depolarization, such that the voltage dependence was right shifted (depolarized) and recovery was hastened. Mutational studies showed this effect was dependent upon the extracellular Ig-like domain, but was independent of the intracellular C-terminal tail. Furthermore, the beta1 effect on slow inactivation was shown to be independent of the negative coupling between fast and slow inactivation.

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness.

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592ValNa+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

A C-terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation.

Missense mutations in the skeletal muscle sodium channel alpha-subunit gene (SCN4A) are associated with a group of clinically overlapping diseases caused by alterations in the excitability of the sarcolemma. Sodium channel defects may increase excitability and cause myotonic stiffness or may render fibres transiently inexcitable to produce periodic paralysis. A patient with cold-aggravated myotonia did not harbour any of the common SCN4A mutations. We therefore screened all 24 exons by denaturing high-performance liquid chromatography, followed by direct sequencing. Two novel missense changes were found with predicted amino acid substitutions: T323M in the DIS5-S6 loop and F1705I in the intracellular C-terminus. The functional impact of these substitutions was assessed by recording whole-cell Na+ currents from transiently transfected HEK293 cells. T323M currents were indistinguishable from wild-type (WT). Fast inactivation was impaired for F1705I channels, as demonstrated by an 8.6-mV rightwards shift in voltage dependence and a two-fold slowing in the rate of inactivation. Recovery from fast inactivation was not altered, nor was there an increase in the persistent current after a 50- ms depolarization. Activation and slow inactivation were not appreciably affected. These data suggest that T323M is a benign polymorphism, whereas F1705I results in fast inactivation defects, which are often observed for myotonia. This is the first example of a C-terminal mutation in SCN4A associated with human disease. Like the cardiac disorders (long QT syndrome type 3 or Brugada syndrome) and generalized epilepsy with febrile seizures plus (GEFS+) associated with C-terminal mutations in other NaV channels, the primary effect of F1705I was a partial disruption of fast inactivation.

Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice.

Myelin-forming oligodendrocytes facilitate saltatory nerve conduction and support neuronal functions in the mammalian CNS. Although the processes of oligodendrogliogenesis and differentiation from neural progenitor cells have come to light in recent years, the molecular mechanisms underlying oligodendrocyte myelinogenesis are poorly defined. Herein, we demonstrate the pivotal role of the basic helix-loop-helix transcription factor, Olig1, in oligodendrocyte myelinogenesis in brain development. Mice lacking a functional Olig1 gene develop severe neurological deficits and die in the third postnatal week. In the brains of these mice, expression of myelin-specific genes is abolished, whereas the formation of oligodendrocyte progenitors is not affected. Furthermore, multilamellar wrapping of myelin membranes around axons does not occur, despite recognition and contact of axons by oligodendrocytes, and Olig1-null mice develop widespread progressive axonal degeneration and gliosis. In contrast, myelin sheaths are formed in the spinal cord, although the extent of myelination is severely reduced. At the molecular level, we find that Olig1 regulates transcription of the major myelin-specific genes, Mbp, Plp1, and Mag, and suppresses expression of a major astrocyte-specific gene, Gfap. Together, our data indicate that Olig1 is a central regulator of oligodendrocyte myelinogenesis in brain and that axonal recognition and myelination by oligodendrocytes are separable processes.

Novel CLCN1 mutations with unique clinical and electrophysiological consequences.

Myotonia is a condition characterized by impaired relaxation of muscle following sudden forceful contraction. We systematically screened all 23 exons of the CLCN1 gene in 88 unrelated patients with myotonia and identified mutations in 14 patients. Six novel mutations were discovered: five were missense (S132C, L283F, T310M, F428S and T550M) found in heterozygous patients, and one was a nonsense mutation (E193X) in a homozygous patient. While five patients had a clinical diagnosis of myotonia congenita, the patient with the F428S mutation exhibited symptoms characteristic of paramyotonia congenita--a condition usually thought to be caused by mutations in the sodium channel gene SCN4A. Nevertheless, no mutations in SCN4A were identified in this patient. The functional consequences of the novel CLCN1 sequence variants were explored by recording chloride currents from human embryonic kidney cells transiently expressing homo- or heterodimeric mutant channels. The five tested mutations caused distinct functional alterations of the homodimeric human muscle chloride ion channel hClC-1. S132C and T550M conferred novel hyperpolarization-induced gating steps, L283F and T310M caused a shift of the activation curve to more positive potentials and F428S reduced the expression level of hClC-1 channels. All showed a dominant-negative effect. For S132C, L283F, T310M and T550M, heterodimeric channels consisting of one wild-type (WT) and one mutant subunit exhibited a shifted activation curve at low intracellular [Cl(-)]. WT-F428S channels displayed properties similar to WT hClC-1, but expressed at significantly lower levels. The novel mutations exhibit a broad variety of functional defects that, by distinct mechanisms, cause a significant reduction of the resting chloride conductance in muscle of heterozygous patients. Our results provide novel insights into functional alterations and clinical symptoms caused by mutations in CLCN1.