Surrounding Needling and Narrowband Ultraviolet B Phototherapy Treatment: Synergistic Effects for Repigmentation in Chronic, Stable Nonsegmental Vitiligo.

Context: Narrowband ultraviolet B (NBUVB) phototherapy is the standard treatment for chronic stable vitiligo, but its efficacy, when used alone, is often unsatisfactory. Objective: The study evaluated the efficacy of surrounding needling with acupuncture needles in combination with NBUVB phototherapy for lesions on different body parts of patients with chronic stable vitiligo. Design: The research team designed a 12-week, randomized, open-label, prospective, intra-individual, comparative clinical trial. Setting: The study took place in the Department of Dermatology at Shin-Kong Wu Ho-Su Memorial Hospital in Taiwan. Participants: Participants were patients at the hospital, aged 20-80 years, with chronic stable nonsegmental vitiligo. The lesions on both sides of their bodies had the same baseline conditions. Nine patients with 14 pairs of lesions (n = 28) were included in the study, and eight participants with 13 pairs of lesions (n = 26) successfully completed the study. Intervention: Vitiligo lesions in the intervention group were treated with surrounding needling combined with NBUVB phototherapy, whereas the control group received NBUVB phototherapy only. Outcome Measures: The primary outcome was evaluated at Week 12 using the modified Vitiligo Area Scoring Index (VASI), which focuses on local depigmentation only without multiplication by body surface area, and the testing used the Wilcoxon signed-rank test. A higher VASI score indicates more severe vitiligo. Pain was rated postintervention, after completion of all treatments. Results: At baseline, the modified VASI score in both groups was 93.07 ± 4.62. Postintervention, this score in the intervention group improved to 78.46 ± 15.24, with a significant difference between baseline and postintervention (P = .007), and in the control group, the score improved to 91.92 ± 6.67, with no significant difference having occurred (P = .317). A statistically significant difference was found between the intervention group and the control group in the change in scores postintervention (P = .007). Conclusion: Surrounding needling in combination with NBUVB phototherapy may be a promising treatment for chronic stable nonsegmental vitiligo. Future studies with larger sample sizes and long-term follow-up are warranted.

Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations.

Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.

Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins.

Massive GGGGCC repeat expansion in the first intron of the gene C9orf72 is the most common known cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Despite its intronic localization and lack of an ATG start codon, the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins, poly-(Gly-Ala), poly-(Gly-Pro) and poly-(Gly-Arg). We took an antibody-based approach to further validate the translation of DPR proteins. To test whether the antisense repeat RNA transcript is also translated, we raised antibodies against the predicted products, poly-(Ala-Pro) and poly-(Pro-Arg). Both antibodies stained p62-positive neuronal cytoplasmic inclusions throughout the cerebellum and hippocampus indicating that not only sense but also antisense strand repeats are translated into DPR proteins in the absence of ATG start codons. Protein products of both strands co-aggregate suggesting concurrent translation of both strands. Moreover, an antibody targeting the putative carboxyl terminus of DPR proteins can detect inclusion pathology in C9orf72 repeat expansion carriers suggesting that the non-ATG translation continues through the entire repeat and beyond. A highly sensitive monoclonal antibody against poly-(Gly-Arg), visualized abundant inclusion pathology in all cortical regions and some inclusions also in motoneurons. Together, our data show that the GGGGCC repeat is bidirectionally translated into five distinct DPR proteins that co-aggregate in the characteristic p62-positive TDP-43 negative inclusions found in FTLD/ALS cases with C9orf72 repeat expansion. Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS.

The prevalence and demographic features of congenital cytomegalovirus infection in an urban area of East Asia: A population-based study.

Congenital cytomegalovirus (cCMV) infection is the leading environmental cause of childhood hearing impairment. However, its significance remains largely undocumented in many regions of the world. The purpose of this study was to investigate the prevalence and clinical features of cCMV infection in East Asia. Neonates born at a municipal hospital in Taipei were prospectively recruited and underwent concurrent hearing and CMV screenings. Those who failed the hearing screening or screened positive for CMV were subjected to a focused audiological and/or virological surveillance. The characteristics of the newborns and their mothers were compared between the CMV-positive and CMV-negative groups. Of the 1,532 newborns who underwent concurrent hearing and CMV screenings, seven (0.46%) were positive for cCMV infection. All seven CMV-positive newborns were asymptomatic at birth, and none of them developed hearing or other symptoms during a follow-up period of 14.4±6.3 months. The mothers of the CMV-positive newborns demonstrated higher gravidity (2.4 ± 1.4 vs. 2.1 ± 1.2) and parity (2.0 ± 1.2 vs. 1.6 ± 0.7) than those in the CMV-negative group; however, the difference did not reach statistical significance. The prevalence of cCMV infection in Taipei newborns was 0.46%, which is slightly lower than that of other populations and that of a previous report in the Taiwanese population. The relatively low prevalence in this study might be attributed to the improved public health system and decreased fertility rate in Taiwan.

Generation of a human iPS cell line (CGMH.SLC26A4919-2) from a Pendred syndrome patient carrying SLC26A4 c.919-2A>G splice-site mutation.

SLC26A4 is the second most frequent gene implicated in congenital hearing loss after GJB2 mutations. Here, we report the generation of induced pluripotent stem cells (iPSCs), from a patient who was carrying a homozygous c.919-2A>G variant in the SLC26A4 gene. This is the most common variant of SLC26A4 gene in the Chinese population and the second most prevalent one in other Asian countries. The established patient-derived iPSC displayed all the features of pluripotent stem cell markers and had the ability to differentiate into all of the three germ layers and possessed a normal karyotype.

Stem cell therapy on skin: Mechanisms, recent advances and drug reviewing issues.

Stem cell products and its clinical applications have been widely discussed in recent years, particularly when the Japanese "induced pluripotent stem cells" founder Dr. Yamanaka was awarded as Nobel Prize laureate in 2013. For decades, major progresses have been achieved in the stem cell biology field, and more and more evidence showed that skin stem cells are involved in the process of skin repair. Stem/progenitor cells of the epidermis are recognized to play the most essential role in the tissue regeneration of skin. In this review, we first illustrated basic stem cell characteristics and various stem cell subtypes resided in the skin. Second, we provided several literatures to elucidate how stem/progenitor cells collaborate in the process of skin repair with the evidence from animal model studies and in vitro experiments. Third, we also introduced several examples of skin cell products on the pharmaceutic market and the ongoing clinical trials aiming for unmet medical difficulties of skin. Last but not least, we summarized general reviewing concerns and some disputatious issues on dermatological cell products. With this concise review, we hope to provide further beneficial suggestions for the development of more effective and safer dermatological stem/progenitor cell products in the future.

Phase-Locked Inhibition, but Not Excitation, Underlies Hippocampal Ripple Oscillations in Awake Mice In Vivo.

Sharp wave-ripple (SWR) oscillations play a key role in memory consolidation during non-rapid eye movement sleep, immobility, and consummatory behavior. However, whether temporally modulated synaptic excitation or inhibition underlies the ripples is controversial. To address this question, we performed simultaneous recordings of excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) and local field potentials (LFPs) in the CA1 region of awake mice in vivo. During SWRs, inhibition dominated over excitation, with a peak conductance ratio of 4.1 ± 0.5. Furthermore, the amplitude of SWR-associated IPSCs was positively correlated with SWR magnitude, whereas that of EPSCs was not. Finally, phase analysis indicated that IPSCs were phase-locked to individual ripple cycles, whereas EPSCs were uniformly distributed in phase space. Optogenetic inhibition indicated that PV+ interneurons provided a major contribution to SWR-associated IPSCs. Thus, phasic inhibition, but not excitation, shapes SWR oscillations in the hippocampal CA1 region in vivo.

Serial sonographic findings of lenticulostriate vasculopathy.

The vessels supplying basal ganglia and thalami are not usually detectable on the neurosonogram in the neonates. In recent studies, bright linear echogenesitis in these regions have been well decribed and were defined as lentriculostriate vasculopathy (LSV). These lesions suggested as a marker of a previous insult to the fetal or neonatal brain and the hemodynamics in the immature brain play an important role in its pathogenesis. In a period of 2 year and 5 months, we collected 39 cases of neonates and prematurities with LSV. These include 16 cases of premature babies, 16 cases of normal full-term neonates and 7 cases with perinatal insults. LSV was detected incidentally in most cases, distinctly different from the previous reports that LSV are linked with congenital anomaly, chromosomal anomaly, prematurity, perinatal insult or congenital infection, etc. There are early onset (< or = 7 days) LSV in 23 cases (59%) and late onset (>7 days) in 16 cases (41%). 16 cases (41%) had total remission, 7 cases (18%) had partial remission, and 16 cases (41%) remained persistantly. Rare reports remined of the long term effect of LSV including tics, attention deficit hyperactive disorder and developmental delay. An isolated LSV generally has a good long term prognosis and a grave neurologic deficit may be mainly due to its associated brain damage.

The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS.

Expansion of a GGGGCC hexanucleotide repeat upstream of the C9orf72 coding region is the most common cause of familial frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD/ALS), but the pathomechanisms involved are unknown. As in other FTLD/ALS variants, characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown. Here, we found that most of these characteristic inclusions contain poly-(Gly-Ala) and, to a lesser extent, poly-(Gly-Pro) and poly-(Gly-Arg) dipeptide-repeat proteins presumably generated by non-ATG-initiated translation from the expanded GGGGCC repeat in three reading frames. These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion.

Rett syndrome: from bed to bench.

Rett syndrome (RTT), a neurodevelopmental condition characterized by delayed-onset loss of spoken language and the development of distinctive hand stereotypies, affects approximately 1 in 10,000 live female births. Clinical diagnosis has been based on symptoms such as loss of acquired purposeful hand skills, autistic behaviors, motor dysfunctions, seizure disorders, and gait abnormalities. RTT is a genetic disease and is caused almost exclusively by mutations in the X-linked gene, MECP2, to produce a phenotype that is thought to be primarily of neurological origin. Clinical reports show RTT patients to have a smaller brain volume, especially in the cerebral hemispheres, and alterations in various neurotransmitter systems, including acetylcholine, dopamine, serotonin, glutamate, substance P, and various trophic factors. Because of its monogenetic characteristic, disruption of Mecp2 is readily recapitulated in mice to produce a prominent RTT-like phenotype and provide an excellent platform for understanding the pathogenesis of RTT. As shown in human studies, Mecp2 mutants also display subtle alterations in neuronal morphology, including smaller cortical neurons with a higher-packing density and reduced dendritic complexity. Neurophysiological studies in Mecp2-mutant mice consistently report alterations in synaptic function, notably, defects in synaptic plasticity. These data suggest that RTT might be regarded as a synaptopathy (disease of the synapse) and thus potentially amenable to rational therapeutic intervention.