Expression of Vincristin-induced Peripheral Neuropathy Related to Different Administration Methods.

Vincristine (VCR) is an important drug used in R-CHOP regimens for the treatment of non-Hodgkin's lymphoma. The purpose of this study was to examine whether the administration method affects the incidence of VCR-induced peripheral neuropathy. We investigated the ratio of VCR-induced peripheral neuropathy during rapid intravenous infusion and intravenous drip infusion. A total of 71 patients who had received six or more courses of R-CHOP from January, 2015 to December, 2016 at Komaki City Hospital and Ogaki Municipal Hospital were retrospectively investigated. Peripheral neuropathy was observed in 27/39 patients (69 %) and 24/32 (75 %) in rapid intravenous infusion and intravenous drip infusion of VCR, respectively (P = 0.79). Peripheral neuropathy was observed at a high frequency in this study. Additionally, there was no difference in frequency of peripheral neuropathy due to the difference in administration method. In both groups, the degree of peripheral neuropathy was grade 1 and grade 2 in most patients. However, in rapid intravenous infusion, grade 3 peripheral neuropathy was observed. Some cases required dose reduction and discontinuation in rapid intravenous infusion. In contrast, there were no discontinuing patients in the intravenous drip infusion. Therefore, it was suggested that intravenous drip infusion of VCR reduced serious peripheral neuropathy because the ratio requiring dose reduction and discontinuation was less than that in the rapid group. In conclusion, this study is informative as there are few reports focusing on the administration method of vincristine.

Association between immune-related dermatologic adverse events and efficacy of pembrolizumab in non-small cell lung cancer patients.

We retrospectively evaluated the incidence of skin immune-related adverse effects (irAEs) in patients treated with pembrolizumab (PMB) and explored and the relationship between skin irAEs and PMB efficacy. Thirty-two patients with non-small cell lung cancer treated with PMB between April 2017 and May 2018 were enrolled. The patients were separated into two groups, namely, skin irAEs and no-skin irAEs group. We investigated the ratio and degree of express skin irAEs, period of skin irAEs and treatment, and the PFS between the two groups. Additionally, we evaluated the PFS between the irAE and no-irAEs groups. The median patient age was 76.5 (range 56-92) years. The European Cooperative Oncology Group Performance Status (ECOG PS) score of 26, 5, and 1 was 0-1, 2, and 3, respectively. The male/female ratio was 23/9. In terms of clinical stages, 6, 21, and 5 patients were in stages III and IV, and postoperative relapse, respectively. Skin irAEs were observed in 10 patients (31%). The progression-free survival of patients with skin irAEs (median, 390 days) was longer than that of patients without skin irAEs (median, 128.5 days). Overall, we suggested a significant association between skin irAEs and the efficacy of PMB in treating non-small cell lung cancer. As skin irAEs can be an indicator of treatment efficacy, it is important for medical staff, including pharmacists, to closely observe these adverse events.

Association between dipeptidyl peptidase-4 inhibitors and autoimmune disorders: Data mining of the spontaneous reporting system in Japan.

The main objective of this study is to conduct a disproportionality analysis of adverse events in the Japan Adverse Event Report (JADER) database and evaluate the risk of the DPP-4 inhibitor induced autoimmune disorder, the secondary objective is risk assessment of sex difference and age difference. The proportional reporting ratio (PRR) of frequency-based statistics and Bayesian estimates of the information components (IC) were calculated as a measure of signal detection. Sex difference and age difference were evaluated using signal score calculated from the PRR and the Chi-square. In patients taking DPP-4 inhibitors, 94 reports of autoimmune disorders were detected with both signals; PRR: 4.09, chi-square: 158.26 and IC: 1.66, 95 % confidence interval: 1.32-2.00). For other antidiabetic drugs, no signals were detected. The signal of males was PRR: 4.53, chi-square: 110.91 and signal score: 6.22, the signal of female was PRR: 3.53, chi-square: 47.65 and signal score: 5.12. About age difference, the signal scores were 6.71 for patients over 60 years and 0.56 for patients under 60 years old. This study suggests that the DPP-4 inhibitors, unlike other antidiabetic drugs, were associated with autoimmune disorders. Signals of the DPP-4 inhibitors induced autoimmune disorders were detected in both male and female, but no sex difference was observed, but age difference was observed. Especially attention should be paid to patients over 60 years old.

Enhanced immunity in intradermal vaccination by novel hollow microneedles.

BACKGROUND: The intradermal (ID) route for vaccination represents an effective alternative to subcutaneous (SC)/intramuscular administration to induce protective immunity. However, a critical issue associated with ID vaccination is the precise delivery of solution in the upper dermis, which ensures enhanced immunity. METHODS: We fabricated a hollow microneedle unit made of poly-glycolic acid by injection molding and bonding, and created a dedicated prototype injector. To ensure ID delivery of solution, the injected site was macroscopically and microscopically examined. Serum immunoglobulin G antibody production was measured by enzyme immunoassay and compared in groups of rats following either ID delivery with microneedles or SC administration with a 27-G stainless needle of graded vaccine doses. RESULTS: The unit used a tandem array of six microneedles, each with a side delivery hole, and a conduit inside for solution. Microneedles installed in the injector punctured the skin with the aid of a spring. Injection of solution formed a wheal due to ID distribution. Histologically, a wedge-shaped skin defect in the upper skin corresponded to each puncture site. Antibody titers following vaccinations on days 1 and 8 were significantly higher with ID injection than with SC delivery on day 15 and every 7 days thereafter until day 36 with mumps vaccination, and until day 36 with varicella vaccination. CONCLUSIONS: The microneedle unit presented here delivered solution intradermally without any difficulty and evoked antibody responses against viruses even with the reduced vaccine volume. Our findings confirm promising results of ID delivery as an immunogenic option to enhance vaccination efficacy.

Femtosecond carrier relaxation dynamics and photoinduced phase separation in κ-(BEDT-TTF)2Cu[N(CN)2]X (X=Br,Cl).

We investigate the relaxation dynamics of nonequilibrium carriers in organic conductors κ-(BEDT-TTF)(2)Cu[N(CN)(2)]X (X=Br and Cl) using ultrafast time-resolved optical spectroscopy. The dynamics for both salts show similar temperature dependences, which is well characterized by the carrier relaxation across the pseudogap (PG) of the magnitude Δ(PG) ≈ 16 meV for Br salt and 7.0 meV for Cl salt. On the other hand, only the Br salt shows an abrupt increase of the decay time at low temperature, indicating an additional decay component associated with the superconducting (SC) gap below T(c). The fluence dependent dynamics at low temperature evidences the superposition of the SC component onto the PG component. These results indicate a metallic-insulating phase separation in the Br salt triggered by photoexcited nonequilibrium carriers.

Neuroradiological and neurofunctional examinations for patients with 22q11.2 deletion.

Since the neuroradiological features of patients with 22q11.2 deletion syndrome are not well-understood, examinations using functional imaging were performed in this study. Brain magnetic resonance imaging (MRI) and 1H-magnetic resonance spectroscopy (MRS) were performed using a clinical 3-Tesla MR imager in 4 patients with 22q11.2 deletion syndrome (2 boys and 2 girls; aged 2-6 years.) and 20 age- and sex-matched healthy control subjects. Furthermore, interictal 123I-iomazenil (IMZ) single photon emission computed tomography (SPECT) was examined in 2 of the 4 patients. Among the 4 patients with 22q11.2 deletion syndrome, 2 patients showed polymicrogyria and 1 patient showed agyria. Those patients with brain malformations also showed abnormal brain artery patterns and decreased accumulation of IMZ in 123I-IMZ SPECT. Although all 4 patients showed epileptic discharges in their electroencephalograms (EEG), one patient with polymicrogyria had no seizure episodes. Decreases in γ-aminobutyric acid (GABA) corresponding to the areas of polymicrogyria and/or epileptic discharges in EEG were shown in all patients except for the patient with agyria. Although consistent evidence was not seen in patients with 22q11.2 deletion syndrome in this study, brain malformations and disturbances of the GABAergic nervous system would be underlying mechanisms of the neurodevelopmental abnormalities in this syndrome.

Dynamics of a paired optical vortex generated by second-harmonic generation.

We study the dynamics of a paired optical vortex (OV) generated by second-harmonic generation (SHG) using sub-picosecond pulses. By changing the position of a thin nonlinear crystal along the propagation direction, we observe a rotation of two vortices with changing separation distance. The dynamics is well explained by SHG with a beam walk-off, which introduces a contamination of zero-order Laguerre-Gaussian beam (LG(0)) together with topological charge doubling. The quantitative analysis indicates that the rotation angle of the OVs manifests the Gouy phase while the splitting provides the walk-off angle of the crystal. We also show that the subtraction of LG(0) is realized by the superposition of LG(0) with an anti-balanced phase in the pump.

Chiral charge-density waves.

We discovered the chirality of charge-density waves (CDW) in 1T-TiSe2 by using STM and time-domain optical polarimetry. We found that the CDW intensity becomes Ia1∶Ia2∶Ia3 = 1∶0.7 ± 0.1∶0.5 ± 0.1, where Ia(i) (i=1,2,3) is the amplitude of the tunneling current contributed by the CDWs. There were two states, in which the three intensity peaks of the CDW decrease clockwise and anticlockwise. The chirality in CDW results in the threefold symmetry breaking. Macroscopically, twofold symmetry was indeed observed in optical measurement. We propose the new generalized CDW chirality H(CDW) ≡ q1·(q2×q3), where q(i) are the CDW q vectors, which is independent of the symmetry of components. The nonzero H(CDW)-the triple-q vectors do not exist in an identical plane in the reciprocal space-should induce a real-space chirality in CDW system.

Frequent MN1 Gene Mutations in Malignant Peripheral Nerve Sheath Tumor.

BACKGROUND/AIM: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft-tissue tumor, and its diagnosis is usually made histopathologically. The effectiveness of chemotherapy and radiotherapy has not been established. We elucidated prognostic factors, diagnostic markers, and therapeutic targets. MATERIALS AND METHODS: Cases of MPNST were studied using next-generation sequencing. A total of 24 tumor samples, 11 from von Recklinghausen's disease-associated MPNST (vRH-MPNST), 11 from sporadic non-vRH MPNST, and two neurofibroma (NF) cases were retrieved, on which next-generation sequencing and survival analysis were performed. RESULTS: We identified NF1 gene mutations, including three mutations in two NFs, and 10 mutations in eight MPNSTs (five vRH-MPNSTs and three sporadic MPNSTs). Meningioma 1 (MN1) gene alteration was detected in six cases of vRH-MPNST. It is considered that MN1 gene alteration is related to the tumorigenesis of vRH-MPNST. CONCLUSION: MN1 gene mutation was detected in more than half of our cases, it may have potential for use as a therapeutic target in vRH-MPNST.

Coherent transfer of orbital angular momentum to excitons by optical four-wave mixing.

We demonstrate the coherent transfer of optical orbital angular momentum (OAM) to the center of mass momentum of excitons in semiconductor GaN using a four-wave mixing (FWM) process. When we apply the optical vortex (OV) as an excitation pulse, the diffracted FWM signal exhibits phase singularities that satisfy the OAM conservation law, which remain clear within the exciton dephasing time (approximately 1ps). We also demonstrate the arbitrary control of the topological charge in the output signal by changing the OAM of the input pulse. The results provide a way of controlling the optical OAM through carriers in solids. Moreover, the time evolution of the FWM with OAM leads to the study of the closed-loop carrier coherence in materials.

Pressure and magnetic field tuned quantum critical point in the Kondo antiferromagnet CePtZn.

We report magnetization, heat capacity and electrical resistivity measurements on CePtZn, which crystallizes in the orthorhombic TiNiSi type structure. Magnetization and electrical resistivity on the iso-structural series of compounds Ce(1-x)La(x)PtZn (x = 0.1, 0.2 0.5 and 1) were also carried out. The electrical resistivity of CePtZn was also measured in external magnetic fields up to 12 T and under pressures up to 2.66 GPa. We find that CePtZn is a dense Kondo lattice, ordering antiferromagnetically at T(N) = 1.7 K, with a comparable Kondo temperature. The magnetic transition temperature, T(N), is continuously suppressed both by the magnetic field and pressure and [Formula: see text] around 5-6 T and at 1.2 GPa, respectively. Non-Fermi liquid behavior of resistivity at 4 T and 1.2 GPa and logarithmic divergence of the heat capacity, C(4f)/T, at 6 T in a limited temperature region strongly suggest the emergence of a quantum critical point as [Formula: see text].

A comparison of intra-articular hyaluronan injection accuracy rates between three approaches based on radiographic severity of knee osteoarthritis.

OBJECTIVE: To compare the accuracy rates of intra-articular hyaluronic acid (HA) injections for osteoarthritis (OA) of the knee between the modified Waddell approach (an anteromedial approach with manipulative ankle traction at 30 degrees of knee flexion), an anteromedial approach with the subjects seated (hereinafter the seated anteromedial approach) and a lateral patellar approach based on the Kellgren-Lawrence (K-L) radiographic grade (II, III and IV). DESIGNS: Fifty patients with knee OA received HA injections through the three approaches. The accuracy rates were confirmed with a single radiograph after injections of a mixture of radiographic contrast medium. RESULTS: In the K-L grade IV cases (n=11), the accuracy rates through the modified Waddell approach (11 out of 11, 100%) were significantly higher than those through the seated anteromedial approach (six out of 11, 55%) and the lateral patellar approach (six out of 11, 55%) (P=0.035). No significant differences were detected in the accuracy rates of the participants classified as grade II (n=21) or III (n=18) cases between the modified Waddell approach (86% and 78%, respectively), the seated anteromedial approach (71% and 56%, respectively) and the lateral patellar approach (86% and 61%, respectively) (P>0.05). CONCLUSION: Although previous studies have been conducted on the accuracy of needle placement into the intra-articular space of the knee, no evaluations were performed with the results categorized by radiographic severity. This study highlighted the need for clinicians to change the approach employed for HA injections, according to the severity of knee OA.

Hyperglycemia and the outcome of pediatric cardiac surgery patients requiring peritoneal dialysis.

OBJECTIVE: To study the nature of the association between glycemia and ICU mortality in pediatric cardiac surgery patients treated with peritoneal dialysis (PD). MATERIALS AND METHODS: Retrospective observational study in the ICU of a tertiary hospital involving forty pediatric cardiac surgery patients treated with PD. We selected patients requiring PD, extracted glucose measurements and nutritional intake data during ICU stay and calculated mean and maximum blood glucose values i) during ICU stay; ii) during dependence on PD; and iii) during independence from PD. We statistically assessed the relationship between glycemia-related variables and ICU mortality. MEASUREMENTS AND RESULTS: Twenty-two patients treated with PD died (mortality 55%). In the PD cohort, 9725 blood glucose measurements were performed (every 3.3 hours on average). The mean glycemia during dependence on PD was significantly higher in non-survivors than survivors (p<0.0001), but not during independence from PD (p=0.49). The area under the receiver operator characteristic curve for the mean glycemia during dependence on PD was significantly greater than that obtained during independence from PD. Even after adjustment for severity of illness using multivariate logistic analysis, the mean glycemia and calorie intake during PD were significant and independent predictors of ICU mortality. CONCLUSIONS: A higher mean blood glucose concentration during PD, but not during PD-free periods was associated with greater ICU mortality. Mean glycemia and calorie intake during PD were significant and independent predictors of ICU mortality.

Glial fibrillary acidic protein (GFAP) and anti-GFAP autoantibody in canine necrotising meningoencephalitis.

To establish clinical markers for canine necrotising meningoencephalitis (NME) and to elucidate its pathogenesis, glial fibrillary acidic protein (GFAP) and anti-GFAP autoantibodies were measured in the cerebrospinal fluid (CSF) of 32 dogs with NME, 23 dogs with other inflammatory central nervous system (CNS) diseases, 27 dogs with miscellaneous CNS diseases and 25 healthy dogs, including five pugs. The dogs with NME had the highest levels of anti-GFAP autoantibodies. The diagnostic sensitivity and specificity of anti-GFAP autoantibodies for NME were 91 per cent and 73 per cent, respectively. Some of the dogs with NME and the healthy pugs, had high CSF concentrations of GFAP, suggesting a breed-specific fragility of astrocytes. The leakage of GFAP and the development of autoimmunity may be key to understanding the pathogenesis of NME.

Prediction of future scotoma on conventional automated static perimetry using frequency doubling technology perimetry.

AIM: To see if scotoma detected with frequency doubling technology (FDT) is confirmed by Humphrey field analyser (HFA) 3 years later. METHODS: Subjects were first examined with the screening C-20-1 program of FDT. The visual field was examined annually for 4 years using HFA program C30-2. The central 58 test points in HFA were assigned to one of the 17 clusters corresponding to FDT test points. Each cluster was represented as the lowest probability symbol of total deviation (TD) of the HFA test points included in the cluster. Clusters were graded normal, suspected scotoma, and scotoma depending on probability of TD-5% or more, 5%-1%, less than 1%, respectively. Relative risk (RR) of abnormality on FDT for future scotoma on HFA was estimated. RESULTS: 80 eyes of 42 patients were followed up for 4 years. While 4.0% of normal clusters of HFA with normal FDT results developed into scotoma cluster, 20.8% of normal clusters with abnormal FDT results developed into scotoma cluster with HFA at the third year. RR for future scotoma was 5.24 (95% CI, 2.75 to 10.0, p<0.05). CONCLUSION: An abnormal result in FDT shows a high risk of future scotoma on HFA after 3 years even if the original HFA perimetry showed normal results.

Heme arginate pretreatment attenuates pulmonary NF-kappaB and AP-1 activation induced by hemorrhagic shock via heme oxygenase-1 induction.

Hemorrhagic shock followed by resuscitation (HSR) induces oxidative stress that leads to acute lung injury. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to play an important role in the protection from oxidative tissue injuries. We previously demonstrated that HO-1 induction by heme arginate (HA), a strong inducer of HO-1, ameliorated HSR-induced lung injury and inflammation. Cellular redox state is known to modulate the DNA biding activity of the transcription factors; nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In the present study, we treated rats with HA (30 mg/kg of hemin) 18 h prior to HSR and examined its effect on the DNA binding activity of NF-kappaB and AP-1 at 1.5 h after HSR. HSR significantly increased the DNA binding activity of NF-kappaB as well as AP-1, while HA pretreatment markedly attenuated the activities of these transcription factors. In contrast, administration of tin mesoporphyrin, a specific competitive inhibitor of HO activity, to HA-pretreated animals abolished the suppressive effect of HA on the activities of NF-kappaB and AP-1, and increased these activities to almost the same level as those in HSR animals. Our findings indicate that HA pretreatment can significantly suppress the increased activity of NF-kappaB and AP-1 induced by HSR by virtue of its ability to induce HO-1. Our findings also suggest that HO-1 induced by HA pretreatment ameliorates HSR-induced lung injury at least in part mediated through the suppression of the activities of these transcription factors.

A 90-day oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, in F344 rats.

A subchronic oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, was performed with groups of 10 male and 10 female F344 rats fed the agent at dietary levels of 0%, 0.2%, 1.0% and 5.0% for 90 days. There were no treatment-related adverse effects with regard to body weight, food and water consumption, urinalysis, ophthalmology, hematology, serum biochemistry, and organ weight data. On clinical observation, red coloring of fur was noted in both sexes of the 1.0% and 5.0% group rats, with red feces observed in all treated group animals, and necropsy revealed all rats of the treated groups to have reddish coloration of the contents of the gastro-intestinal tract, due to the pigmentation and thus lacking toxicological significance. On histopathological examination, sporadic spontaneous lesions known to occur in this strain of rats were the only findings, with no specific relation to the test substance. Thus, the no-observed-adverse-effect-level (NOAEL) was judged to be a dietary level of at least 5.0% (3127 mg/kg body weight/day for males, 3362 mg/kg body weight/day for females) for beta-carotene derived from B. trispora under the present experimental conditions.

Evaluation of biliary and pancreatic function in pancreolithiasis. Value of the determination of gamma-glutamyl transpeptidase.

Ten patients with pancreolithiasis and ten controls underwent a 110-minute pancreozymin-secretion test in which post-pancreozymin collection periods were prolonged to 30 minutes. Gamma-Glutamyl transpeptidase concentrations and outputs of duodenal aspirate in response to pancreozymin and to secretin were greatly increased in patients with pancreolithiasis. No correlation was noted between gamma-glutamyl transpeptidase and bile pigment concentrations. The mean concentrations and outputs of amylase in disease were much less than those in control subjects throughout the test. Two categories of pancreolithiasis were distinguished with respect to the distribution and size of the calculi and amylase secretion. We suggest that, in pancreolithiasis, there is an increase in ductal or centroacinar cell mass.

Lean body mass and body fat distribution in participants with chronic low back pain.

BACKGROUND: Loss of muscle mass and central obesity progress with aging, but the effect of muscle loss on chronic low back pain has not been precisely evaluated. METHODS: Three hundred thirty Japanese persons aged 45 to 69 years, with a complaint of low back pain for longer than 3 months (n = 203) and age- and sex-matched healthy control subjects (n = 127), were enrolled in this study. Participants with chronic low back pain were classified into the following groups: (1) women with a positive straight leg raise test result, (2) women with a negative straight leg raise test result, (3) men with a positive straight leg raise test result, and (4) men with a negative straight leg raise test result. Controls were classified by sex into a female and a male group. Anthropometric data, consisting of body mass index, percentage body fat, waist-hip ratio, and lean body mass of the upper extremities, trunk, and lower extremities divided by body weight, were measured in participants with low back pain, and the results were compared with those of controls. RESULTS: The waist-hip ratio in women with a negative straight leg raise test result was significantly higher than those in the female control group (P<.001) and in the women with a positive straight leg raise test result (P =.04). The lean body mass of the trunk and lower extremities divided by body weight of women with a negative straight leg raise test result was significantly lower than that of female controls (P =.03 for the trunk and P<.001 for the lower extremities). However, no significant differences were detected between the female negative straight leg raise test result group and the female control group for lean body mass of the upper extremities divided by body weight or body mass index. There were no significant differences in anthropometric data between the male test and control groups or between the female positive straight leg raise test result group and the female control group. CONCLUSION: Trunk and lower extremity loss of muscle mass and central obesity may be risk factors for chronic low back pain without a positive straight leg raise test result in women aged 45 to 69 years. Arch Intern Med. 2000;160:3265-3269.

Evidence for carrier localization in the pseudogap state of cuprate superconductors from coherent quench experiments.

A 'pseudogap' was introduced by Mott to describe a state of matter that has a minimum in the density of states at the Fermi level, deep enough for states to become localized. It can arise either from Coulomb repulsion between electrons, and/or incipient charge or spin order. Here we employ ultrafast spectroscopy to study dynamical properties of the normal to pseudogap state transition in the prototype high-temperature superconductor Bi2Sr2CaCu2O8+δ. We perform a systematic temperature and doping dependence study of the pseudogap photodestruction and recovery in coherent quench experiments, revealing marked absence of critical behaviour of the elementary excitations, which implies an absence of collective electronic ordering beyond a few coherence lengths on short timescales. The data imply ultrafast carrier localization into a textured polaronic state arising from a competing Coulomb interaction and lattice strain, enhanced by a Fermi surface instability.