Impact of a novel pre-hospital stroke notification programme on acute stroke care key performance indicators in Hong Kong: a multicentre prospective cohort study with historical controls.

INTRODUCTION: Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. METHODS: This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. RESULTS: Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. CONCLUSION: Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.

Adverse Drug Event Profile Associated with Anti-dementia Drugs: Analysis of a Spontaneous Reporting Database.

Adverse drug events (ADEs) rates associated with anti-dementia acetylcholinesterase inhibitors are estimated to be 5%-20% and show a wide range of symptoms. No report has examined whether there is a difference in the anti-dementia drugs' ADEs profile. This study aimed to establish whether anti-dementia drugs' ADEs profile differed. Data was based on the Japanese Adverse Drug Event Report (JADER) database. The reporting odds ratios (RORs) was used to analyze data for ADEs from April 2004-October 2021. The target drugs were donepezil, rivastigmine, galantamine, and memantine. The top ten most frequently occurring adverse events were selected. The association between the RORs and antidementia drug ADEs was evaluated, and compared the distribution rate of expression age related to ADEs and each ADEs' timing of onset due to anti-dementia drugs. The primary outcome was RORs. Secondary outcome were expression age and time-to-onset of ADE associated with anti-dementia drugs. A total of 705,294 reports were analyzed. The adverse events incidence differed. Bradycardia, loss of consciousness, falls, and syncope incidence were significantly diverse. The Kaplan-Meier curve results for the cumulative ADEs incidence showed that donepezil had the slowest onset, while galantamine, rivastigmine, and memantine had approximately the same timing of onset.

A case of recurrent acute febrile neutrophilic dermatosis in a patient with idiopathic cytopenia of undetermined significance.

This is the first report of recurrent acute febrile neutrophilic dermatosis in a patient with idiopathic cytopenia of undetermined significance. The patient progressed to acute myeloid leukaemia 4 months after onset.

A comparison of thyroidal protection by iodine and perchlorate against radioiodine exposure in Caucasians and Japanese.

Radioactive iodine released in nuclear accidents may accumulate in the thyroid and by irradiation enhances the risk of cancer. Radioiodine uptake into the gland can be inhibited by large doses of stable iodine or perchlorate. Nutritional iodine daily intake may impact thyroid physiology, so that radiological doses absorbed by the thyroid as well as thyroid blocking efficacy may differ in Japanese with a very rich iodine diet compared to Caucasians. Based on established biokinetic-dosimetric models for the thyroid, we derived the parameters for Caucasians and Japanese to quantitatively compare the effects of radioiodine exposure and the protective efficacy of thyroid blocking by stable iodine at the officially recommended dosages (100 mg in Germany, 76 mg in Japan) or perchlorate. The maximum transport capacity for iodine uptake into the thyroid is lower in Japanese compared to Caucasians. For the same radioiodine exposure pattern, the radiological equivalent thyroid dose is substantially lower in Japanese in the absence of thyroid blocking treatments. In the case of acute radioiodine exposure, stable iodine is less potent in Japanese (ED50 = 41.6 mg) than in Caucasians (ED50 = 2.7 mg) and confers less thyroid protection at the recommended dosages because of a delayed responsiveness to iodine saturation of the gland (Wolff-Chaikoff effect). Perchlorate (ED50 = 10 mg in Caucasians) at a dose of 1000 mg has roughly the same thyroid blocking effect as 100 mg iodine in Caucasians, whereas it confers a much better protection than 76 mg iodine in Japanese. For prolonged exposures, a single dose of iodine offer substantially lower protection than after acute radioiodine exposure in both groups. Repetitive daily iodine administrations improve efficacy without reaching levels after acute radioiodine exposure and achieve only slightly better protection in Japanese than in Caucasians. However, in the case of continuous radioiodine exposure, daily doses of 1000 mg perchlorate achieve a high protective efficacy in Caucasians as well as Japanese (> 0.98). In Caucasians, iodine (100 mg) and perchlorate (1000 mg) at the recommended dosages seem alternatives in case of acute radioiodine exposure, whereas perchlorate has a higher protective efficacy in the case of longer lasting radioiodine exposures. In Japanese, considering protective efficacy, preference should be given to perchlorate in acute as well as prolonged radioiodine exposure scenarios.

The efficacy of synthetic pseudo-ceramide for dry and rough lips.

OBJECTIVE: Lips can easily become dry and rough, one reason being the characteristics of their ceramide (CER) profile. Lips have lower levels of total ceramides, higher percentages of CER[NS] and CER[AS], and lower percentages of CER[NP] and CER[NH] than skin in other regions of the body. The purpose of this study was to clarify the effects of synthetic pseudo-ceramide (pCer; Cetyl-PG hydroxyethyl palmitamide) to improve the dryness and roughness of the lips of healthy subjects in a formulation that exclude an occlusive effect. METHODS: Thirty-one Japanese female subjects with normal skin (age range 21-37 years; mean 28.6) were enrolled in this study. A four-week continuous use test was conducted using samples with or without 0.5% or 2.0% pCer. The degree of lip roughness was scored, and values of capacitance, transepidermal water loss (TEWL) and lip surface elasticity were measured. Endogenous CER profiles and absorption levels of pCer in the stratum corneum (SC) were analysed in tape-stripped skin specimens. RESULTS: Treatment with the pCer-2.0% sample significantly improved the visual roughness score after 2 and 4 weeks compared to 0 weeks and compared to the Blank. Moreover, an improvement in TEWL was observed after 4 weeks of treatment with the pCer-2.0% sample. CER[NP] showed a significant increase in pCer-2.0% treated lips after 4 weeks compared to the Blank. Both pCer-0.5% and pCer-2.0% were significantly absorbed after 2 weeks compared with the Blank. CONCLUSION: The effect of the synthetic pseudo-ceramide pCer to improve the roughness of lips was shown excluding the effect of occlusiveness derived from the formulation for the first time. Since the improvement of TEWL and absorption of pCer was observed, we concluded that pCer was first absorbed in rough lip areas, improved the ceramide profile and consequently restored the barrier function.

OBJECTIF: Les lèvres peuvent facilement devenir sèches et rugueuses, l'une des raisons étant les caractéristiques de leur profil de céramide (CER). Les lèvres présentent des taux plus faibles de céramides totaux, des pourcentages plus élevés de CER[NS] et de CER[AS] et des pourcentages plus faibles de CER[NP] et CER[NH] que la peau des autres régions de l'organisme. L'objectif de cette étude visait à clarifier les effets du pseudo-céramide synthétique (pCer; cétyl-PG hydroxyéthyl palmitamide) pour améliorer la sécheresse et la rugosité des lèvres de sujets en bonne santé avec une formulation excluant un effet occlusif. MÉTHODES: Trente et un sujets de sexe féminin japonais ayant une peau normale (tranche d'âge: 21 à 37 ans; moyenne: 28,6 ans) ont été inclus dans cette étude. Une analyse d'utilisation continue de quatre semaines a été effectuée en employant des échantillons avec ou sans pCer à 0,5 % ou 2,0 %. Le degré de rugosité des lèvres a été noté et les valeurs de capacitance, de perte d'eau transépidermique (transepidermal water loss, TEWL) et d'élasticité de la surface des lèvres ont été mesurées. Les profils CER endogènes et les niveaux d'absorption de pCer de la couche cornée (stratum corneum, SC) ont été analysés dans des échantillons cutanés fixés par bande adhésive. RÉSULTATS: Le traitement avec l'échantillon pCer-2,0% a amélioré de façon significative le score de rugosité visuelle après 2 et 4 semaines par rapport à 0 semaine et par rapport au groupe témoin. En outre, une amélioration de la TEWL a été observée après 4 semaines de traitement avec l'échantillon pCer-2,0%. Après 4 semaines, le CER[NP] a aumenté de manière significative dans les lèvres traitées avec pCer-2,0% par rapport au groupe témoin. Le pCer-0,5 % et le pCer-2,0% ont tous deux été absorbés de manière significative après 2 semaines par rapport au groupe témoin. CONCLUSION: L'effet du pseudo-céramide synthétique pCer pour améliorer la rugosité des lèvres a été démontré, excluant l'effet de l'occlusion dérivé de la formulation pour la première fois. Puisque l'amélioration de la TEWL et l'absorption du pCer ont été observées, nous avons conclu que le pCer était d'abord absorbé dans les zones rugueuses des lèvres, améliorait le profil du céramide et, par conséquent, rétablissait la fonction barrière.

The suppressive effect on CD4 T cell alloresponse against endothelial HLA-DR via PD-L1 induced by anti-A/B ligation.

While donor-specific human leukocyte antigen (HLA) antibodies are a frequent cause for chronic antibody-mediated rejection in organ transplantation, this is not the case for antibodies targeting blood group antigens, as ABO-incompatible (ABO-I) organ transplantation has been associated with a favorable graft outcome. Here, we explored the role of CD4 T cell-mediated alloresponses against endothelial HLA-D-related (DR) in the presence of anti-HLA class I or anti-A/B antibodies. CD4 T cells, notably CD45RA-memory CD4 T cells, undergo extensive proliferation in response to endothelial HLA-DR. The CD4 T cell proliferative response was enhanced in the presence of anti-HLA class I, but attenuated in the presence of anti-A/B antibodies. Microarray analysis and molecular profiling demonstrated that the expression of CD274 programmed cell death ligand 1 (PD-L1) increased in response to anti-A/B ligation-mediated extracellular signal-regulated kinase (ERK) inactivation in endothelial cells that were detected even in the presence of interferon-γ stimulation. Anti-PD-1 antibody enhanced CD4 T cell proliferation, and blocked the suppressive effect of the anti-A/B antibodies. Educated CD25+ CD127- regulatory T cells (edu.Tregs ) were more effective at preventing CD4 T cell alloresponses to endothelial cells compared with naive Treg ; anti-A/B antibodies were not involved in the Treg -mediated events. Finally, amplified expression of transcript encoding PD-L1 was observed in biopsy samples from ABO-I renal transplants when compared with those from ABO-identical/compatible transplants. Taken together, our findings identified a possible factor that might prevent graft rejection and thus contribute to a favorable outcome in ABO-I renal transplantation.

Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS: The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS: The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION: Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.

ANTECEDENTES: La quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales. MÉTODOS: Se evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global. RESULTADOS: Las dosis recomendadas de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2 , respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0-22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes. CONCLUSIÓN: Agregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878).

Correction to: Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta.

The original article has been corrected.

Does preoperative enteral nutrition reduce the incidence of surgical complications in patients with Crohn's disease? A case-matched study.

AIM: Currently, the notion that preoperative optimization with enteral nutrition (EN) reduces the incidence of complication after surgery in Crohn's disease (CD) patients is being debated. This case-matched study was to evaluate the impact of preoperative EN on surgical outcomes in patients with CD. METHOD: Twenty-four patients received EN therapy with an elemental diet (1800-2400 kcal/day) for at least 2 weeks before the planned surgery (EN group). A further 24 patients who underwent surgery without receiving preoperative EN or parenteral nutrition formed a control group based on four matched criteria: age (≤/>40 years), the use of preoperative medications (corticosteroids/azathioprine/biologics), disease behaviour (inflammatory/stricturing/penetrating) and main surgical procedure (ileal resection/ileocolonic resection/colectomy). The incidence of complications observed within 30 days after surgery was compared between the two groups. Septic complications were defined as anastomotic leak, intra-abdominal abscess, entero-cutaneous fistula or wound infection. RESULTS: In the EN group, the median serum albumin level significantly increased, while C-reactive protein (CRP) significantly decreased during the preoperative EN (albumin, from 3.0 mg/dl to 3.1 mg/dl, P = 0.04; CRP, from 3.05 mg/dl to 2.52 mg/dl, P = 0.02). The incidence of postoperative septic complications was significantly lower in the EN group compared with the control group (4% vs 25%, P = 0.04). The occurrence rate of overall complications was lower in the EN group (21% vs 29%, P = 0.51), but not statistically significant. CONCLUSION: In patients with CD, preoperative optimization with EN reduced the overall rate of postoperative complications and significantly decreased postoperative septic complications.

Efficacy of guselkumab in a subpopulation with pustulotic arthro-osteitis through week 52: an exploratory analysis of a phase 3, randomized, double-blind, placebo-controlled study in Japanese patients with palmoplantar pustulosis.

BACKGROUND: Previous studies of guselkumab have demonstrated clinical benefits in patients with plaque-type psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis (PPP). OBJECTIVE: The aim of this exploratory analysis of a double-blind, multicenter, placebo-controlled, phase 3 study in Japanese patients with PPP was to evaluate the efficacy of guselkumab in the subset of patients with pustulotic arthro-osteitis (PAO). METHODS: Patients were randomized to receive guselkumab 100 or 200 mg at weeks 0, 4, 12 and every 8 weeks, or placebo with cross-over to guselkumab 100 or 200 mg at week 16 (placebo group). Efficacy endpoints were changes from baseline in magnetic resonance imaging (MRI) score, EuroQOL-5 dimensions (EQ-5D) index score, EQ-5D pain/discomfort dimension score and C-reactive protein (CRP, mg/L) level in all PAO patients through week 52. Data from both guselkumab groups were combined and presented as results for a single overall guselkumab group. RESULTS: Among 159 patients with PPP, 66 with PAO were randomized across treatment groups. For patients with MRI data for all regions assessed, the proportion of patients in the guselkumab group with PAO characterized as severe decreased from 23.8% (10/42) at baseline to 5.4% (2/42) at week 52. The mean (SD) change from baseline at week 52 in EQ-5D index score was 0.20 (0.17) among PPP patients with PAO and 0.15 (0.17) among those without PAO in the guselkumab group. Among all PAO patients, the proportions with an EQ-5D pain/discomfort dimension score of no or slight pain/discomfort in the guselkumab group increased from baseline to week 52 [33.3% (7/21) vs. 87.5% (35/40)]. The mean (SD) CRP levels decreased in all PAO patients in the guselkumab group at week 52 compared to baseline [-1.71 (8.16) mg/L]. CONCLUSION: Guselkumab treatment showed beneficial outcomes for PAO signs and symptoms in Japanese patients with PPP.

The efficacy of a highly occlusive formulation for dry lips.

OBJECTIVE: Since skin on the lips has a lower water content in the stratum corneum (SC) and a higher transepidermal water loss (TEWL) value than skin on the cheek, the lips are usually very dry and rough areas. Therefore, a lip balm approach to increase occlusivity of the lips is generally used to reduce water loss. Although there have been reports of an improvement effect on lip roughness by specific care agents, differences in the effects due to the occlusivity of a formulation without a specific care agent have not been reported. The purpose of this study was to clarify the improvement effect on dryness and roughness of the lips by a highly occlusive formulation consisting of a combination of common oil and wax, not by a specific care agent. METHODS: Twenty Japanese female subjects with normal skin (age range 20-39 years; mean 28.1) were enrolled in this study. A 4-week continuous use test was conducted using samples with low and high occlusivity. The degree of lip roughness and wrinkles was scored, the hollow index was assessed using ANTERA 3D images, and values of capacitance and TEWL were measured. RESULTS: The hollow index was significantly correlated with both the appearance roughness score and the wrinkle score. The sample with high occlusivity showed significant improvement in the appearance roughness score, wrinkle score, the hollow index and capacitance of the SC. In a comparison between the groups of samples with different occlusive properties, a significant improvement effect in rough appearance was seen in subjects using the highly occlusive formulation. CONCLUSION: The hollow index assessed by ANTERA 3D imaging allowed the objective evaluation of the improvement in appearance. In the case of continuous use of the highly occlusive formulation, an improvement of capacitance in the SC, which is most correlated with lip roughness, was obtained after 2 and 4 weeks. These results demonstrate for the first time that a highly occlusive formulation is effective in improving the roughness of the lips, and this effect is due to the difference in the occlusive property not by a specific care agent.

OBJECTIF: La peau qui recouvre les lèvres ayant une plus faible teneur en eau dans la couche cornée (CC) et une valeur de perte d'eau transépidermique (PETE) plus élevée que la peau des joues, les lèvres sont généralement des zones très sèches et rugueuses. Par conséquent, l'utilisation d'un baume à lèvres pour augmenter l'occlusivité des lèvres est généralement l'approche adoptée pour réduire la perte d'eau. Même s'il y a eu des rapports d'un effet d'amélioration de la rugosité des lèvres grâce à des agents de soin spécifiques, aucune différence par rapport aux effets dus aux propriétés occlusives d'une formule ne contenant pas un agent de soin spécifique n'a été rapportée. Le but de cette étude était de clarifier l'effet d'amélioration de la sécheresse et de la rugosité des lèvres d'une formule hautement occlusive composée d'une association d'huile et de cire courantes, et non pas d'un agent de soin spécifique. MÉTHODES: Vingt sujets de sexe féminin japonais ayant une peau normale (tranche d'âge : 20 à 39 ans ; moyenne : 28,1) ont été inclus dans cette étude. Un test d'utilisation continue pendant 4 semaines a été mené en utilisant des échantillons ayant des propriétés occlusives faibles et élevées. Le degré de rugosité et de ridules des lèvres a été noté, l'indice de creux a été évalué à l'aide d'images 3D ANTERA, et les valeurs de capacitance et de PETE ont été mesurées. RÉSULTATS: L'indice de creux était significativement corrélé avec le score de l'aspect de rugosité et le score de ridules. L'échantillon comportant des propriétés occlusives élevées a démontré une amélioration significative du score de l'aspect de rugosité, du score de ridules, de l'indice de creux et de la capacitance de la CC. Dans une comparaison entre les groupes d'échantillons comportant différentes propriétés occlusives, une amélioration significative de l'effet sur l'aspect rugueux a été observée chez les sujets utilisant la formule aux propriétés occlusives élevées. CONCLUSION: L'indice de creux évalué par l'imagerie 3D ANTERA a permis d'effectuer une évaluation objective de l'amélioration de l'aspect. Dans le cas d'une utilisation continue de la formule aux propriétés occlusives élevées, une amélioration de la capacitance de la CC, qui était le plus corrélée avec la rugosité des lèvres, a été atteinte au bout de 2 et 4 semaines. Ces résultats montrent pour la première fois qu'une formule aux propriétés occlusives élevées est efficace dans l'amélioration de la rugosité des lèvres, et cet effet est dû à la différence dans les propriétés occlusives et non pas à un agent de soin spécifique.

Comprehensive genetic analyses using targeted next-generation sequencing and genotype-phenotype correlations in 53 Japanese patients with osteogenesis imperfecta.

To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed comprehensively in this patient population. Most mutations were located on COL1A1 and COL1A2. Glycine substitutions in COL1A1 resulted in the severe phenotype. INTRODUCTION: Most cases of osteogenesis imperfecta (OI) are caused by mutations in COL1A1 or COL1A2, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS). METHODS: We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families. RESULTS: Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in COL1A1 (n = 30, 69.8%), COL1A2 (n = 12, 27.9%), and IFITM5 (n = 1, 2.3%). Patients with glycine substitution on COL1A1 had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions. CONCLUSION: We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on COL1A1 and COL1A2. This study revealed that glycine substitutions on COL1A1 resulted in the severe phenotype among Japanese patients with OI.

Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential.

Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a µ/δ opioid agonist and NK1R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist-NK1R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

A case of generalized pustular psoriasis caused by hydroxychloroquine in a patient with systemic lupus erythematosus.

Hydroxychloroquine (HCQ) has been used to treat systemic lupus erythematosus (SLE) in Japan since 2015. We herein report a case of SLE that developed generalized pustular psoriasis (GPP) following the administration of HCQ. Twenty-one days after the HCQ treatment, a pustular rash with itching appeared on the auricle, scalp, and forearm, and spread rapidly to the face and body trunk with a high fever and arthralgia. Skin biopsy showed pustule formation under the cornified layer, neutrophil infiltration, the destruction of keratinocytes, and spongiform pustules of Kogoj. The patient was diagnosed with GPP. HCQ was immediately discontinued, the dose of prednisolone (PSL) was increased, and granulocyte and monocyte adsorption apheresis was performed. Her symptoms subsequently disappeared. Since arthralgia relapsed after the tapering of PSL, cyclosporine was added. Although single nucleotide polymorphisms (c.28C>T and c.115+6T>C) in the interleukin (IL)-36RN gene, which encodes the IL-36 receptor antagonist, have frequently been reported in GPP, these mutations were not observed in the present case. The potential development of GPP needs to be considered when administering HCQ to patients with SLE.

Removal of carbon contamination in ETEM by introducing Ar during electron beam irradiation.

Organic materials, including carbon, exist inside the transmission electron microscope (TEM) chamber and are adsorbed onto samples under observation during TEM. When these adsorbed organic materials are irradiated by an electron beam, the adsorbed gas is decomposed. Carbon atoms remain on the sample and bond with each other forming a material with an amorphous structure. Due to the carbon deposition on the observation area of the sample, it is contaminated and the TEM image quality is decreased. Ar was introduced into environmental TEM (ETEM) to purge organic material from the sample chamber to reduce contamination growth. After Ar gas was introduced, the contamination was gradually removed. The contamination removal rate was dependent on the Ar pressure. Moreover, it was clear that Ar was ionised by electron beam irradiation and the Ar ions were produced in the ETEM during electron beam irradiation. It is proposed that the Ar ions removed the carbon contamination. LAY DESCRIPTION: Organic materials, including carbon, exist inside the transmission electron microscope (TEM) chamber and are adsorbed onto samples under observation during TEM. When these adsorbed organic materials are irradiated by an electron beam, the adsorbed gas is decomposed. Carbon atoms remain on the sample and bond with each other forming a material with an amorphous structure. Due to the carbon deposition on the observation area of the sample, it is contaminated and the TEM image quality is decreased. Ar was introduced into environmental TEM (ETEM) to purge organic material from the sample chamber to reduce contamination growth. After Ar gas was introduced, the contamination was gradually removed. The contamination removal rate was dependent on the Ar pressure. Moreover, it was clear that Ar was ionised by electron beam irradiation and the Ar ions were produced in the ETEM during electron beam irradiation. It is proposed that the Ar ions removed the carbon contamination.

Impact of reconstruction parameters on quantitative bone SPECT imaging: A novel thoracic spine phantom study.

INTRODUCTION: The aim of this study was to validate the effect of reconstruction parameters on quantitative accuracy of bone single-photon emission computed tomography (SPECT) images using a novel thoracic spine phantom. METHODS: We used a novel thoracic spine phantom for bone SPECT image evaluation. This phantom consisted of a body, a vertebral body, a spinous process, and a tumor part (spheres, diameter: 13, 17, 22, 28mm), which were filled with 99mTc and bone-equivalent solution. The SPECT/CT images were acquired with a dual-head SPECT/CT camera (Infinia8 Hawkeye 4, GE) equipped with low-energy high resolution collimator. The bone phantom images were reconstructed using the ordered subset expectation maximization (OSEM) algorithm with resolution recovery and CT-based attenuation correction and scatter correction. The number of iterations was varied from 1 to 20 and the number of subsets was fixed at 10. The maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, SUVmean) were calculated for the body and the tumor part, and the relative measurement error was assessed. RESULTS: All quantitative values increased as the number of iterations increased and reached plateaus at 50-100 update numbers. The SUVmax of tumor part was 59.2 when the number of iterations was 2 and 55.7 when the number of iterations was 20. The maximum relative measurement error on the tumor part (reference value: 50) was obtained using the number of iteration 1 and over 10. CONCLUSION: Our results indicated that the quantitative accuracy of bone SPECT images was affected by reconstruction parameters. It is important to optimize the reconstruction parameters, and improve quantitative accuracy in bone SPECT imaging.