Seasonal and diurnal variations in soil respiration rates at a treeline ecotone and a lower distribution limit of subalpine forests.

This study examined the seasonal and diurnal variations in soil respiration rates (RS) during a growing season at the treeline ecotone (2,800 m) and the lower distribution limit (1,600 m) of subalpine forests on a volcanic mountain in Japan. The aboveground biomass, the total RS during the growing season, and the RS per day during the growing season were lower at 2,800 m than those at 1,600 m. Seasonal RS variations positively correlated with those of soil and air temperatures at both elevations, and this tendency was more apparent at 1,600 m than 2,800 m. The mean volumetric soil water content (WS) during the growing season was much lower at 2,800 m than 1,600 m because of the scoria substrate at 2,800 m. The monthly mean diel cycle of RS was positively correlated with the soil temperature at each elevation every month, whereas that at 1,600 m was negatively correlated with that of the WS. The RS at 2,800 m decreased during the daytime especially in August, despite no changes in the WS. The decrease in RS after precipitation at 1,600 m was higher than that at 2,800 m. Seasonal and diurnal RS variations could be reproduced from soil and air temperatures, and WS. Estimating soil respiration rate from these variables will help understand the future carbon budget of forests due to global warming.

Sequential detection rates of intramural hematoma for diagnosing spontaneous intracranial artery dissection.

BACKGROUND AND PURPOSE: Spontaneous intracranial artery dissection (IAD) can be definitively diagnosed by detecting intramural hematoma (IMH) on arterial wall imaging. However, evidence of a time-dependent natural history for the development of radiological findings is lacking. Therefore, this study aimed to determine when imaging detects IAD. METHODS: We obtained data from our cohort databases between March 2011 and August 2018 on consecutive patients who had definite, probable, or possible IAD based on the multidisciplinary expert consensus criteria. We assessed IMH on initial and follow-up high-resolution three-dimensional T1-weighted imaging (HR-3D-T1WI). We retrospectively investigated the association between IMH detection and days from symptom onset to initial HR-3D-T1WI and compared the IMH detection rate with other definitive diagnostic arterial dissection findings. RESULTS: We analyzed 106 patients (mean age = 51 ± 13 years, 31 women) with at least initial HR-3D-T1WI data. The final diagnoses were definite, probable, and possible IAD in 83, 18, and 5 patients, respectively. IMHs were observed in 63 patients (59%, 95% confidence interval [CI] = 49%-69%). Overall IMH detection rate was 55% (95% CI = 45%-64%), 20% (95% CI = 3%-60%), 40% (95% CI = 21%-64%), and 50% (95% CI = 37%-63%) on the initial HR-3D-T1WI and Days 3, 7, and 13, respectively. Among 68 patients evaluated with digital subtraction angiography and HR-3D-T1WI, IMH was confirmed more frequently than other definitive diagnostic arterial dissection findings. CONCLUSIONS: The overall IMH detection rate on HR-3D-T1WI was >50% and peaked in 1-2 weeks. IMH was a frequently detectable finding for the diagnosis of IAD compared to other radiological findings.

Early high-dose intravenous immunoglobulin for refractory heparin-induced thrombocytopenia with stroke: Two case reports.

BACKGROUND: High-dose intravenous immunoglobulin (IVIg) can be effective for patients with refractory autoimmune heparin-induced thrombocytopenia (HIT). We report two patients with autoimmune HIT (aHIT) successfully treated with early high-dose IVIg. CASE DESCRIPTION: Case 1 was a 48-year-old male who had persisting HIT with recurrent ischemic stroke after mitral valve replacement. Case 2 was a 71-year-old male who had flush heparin HIT with cerebral venous thrombosis after total hip arthroplasty. High-dose IVIg was administered 6 and 4 days after starting argatroban due to non-improved thrombocytopenia and persistently high D-dimer values, respectively. Both patients achieved favorable functional recovery at discharge as well as improvements of thrombocytopenia and hypercoagulation. CONCLUSIONS: Early high-dose IVIg may be effective for patients with aHIT and hypercoagulability.

Anatomical patterns of condensed tannin in fine roots of tree species from a cool-temperate forest.

BACKGROUND AND AIMS: Condensed tannin (CT) is an important compound in plant biological structural defence and for tolerance of herbivory and environmental stress. However, little is known of the role and location of CT within the fine roots of woody plants. To understand the role of CT in fine roots across diverse species of woody dicot, we evaluated the localization of CT that accumulated in root tissue, and examined its relationships with the stele and cortex tissue in cross-sections of roots in 20 tree species forming different microbial symbiotic groups (ectomycorrhiza and arbuscular mycorrhiza). METHODS: In a cool-temperate forest in Japan, cross-sections of sampled roots in different branching order classes, namely, first order, second to third order, fourth order, and higher than fourth order (higher order), were measured in terms of the length-based ratios of stele diameter and cortex thickness to root diameter. All root samples were then stained with ρ-dimethylaminocinnamaldehyde solution and we determined the ratio of localized CT accumulation area to the root cross-section area (CT ratio). KEY RESULTS: Stele ratio tended to increase with increasing root order, whereas cortex ratio either remained unchanged or decreased with increasing order in all species. The CT ratio was significantly positively correlated to the stele ratio and negatively correlated to the cortex ratio in second- to fourth-order roots across species during the shift from primary to secondary root growth. Ectomycorrhiza-associated species mostly had a higher stele ratio and lower cortex ratio than arbuscular mycorrhiza-associated species across root orders. Compared with arbuscular mycorrhiza species, there was greater accumulation of CT in response to changes in the root order of ectomycorrhiza species. CONCLUSIONS: Different development patterns of the stele, cortex and CT accumulation along the transition from root tip to secondary roots could be distinguished between different mycorrhizal associations. The CT in tissues in different mycorrhizal associations could help with root protection in specific branching orders during shifts in stele and cortex development before and during cork layer formation.

Elevated CA125 is Related to Stroke Due to Cancer- Associated Hypercoagulation.

BACKGROUND: Cancer-associated hypercoagulation is one of the major pathophysiological mechanisms of stroke in cancer patients. Carcinomatous mucins are considered to play an important role in cancer-associated hypercoagulation. Therefore, carbohydrate antigen-125 (CA125), which is a typical mucin molecule and mucin-producing tumor marker, may be related to stroke due to cancer-associated hypercoagulation. AIMS: We aimed to clarify the association of CA125 with a hypercoagulable state in acute stroke patients with active cancer. METHODS: We studied 77 acute ischemic stroke patients with active cancer who had undergone CA125 measurement. The study patients were categorized into hypercoagulation or non-hypercoagulation groups. The hypercoagulation group was defined as stroke patients with a D-dimer value exceeding 3 µg/mL and multiple vascular territory infarcts. Elevation of tumor markers was defined as values more than twice the upper limit of the normal range. RESULTS: Forty-five (58%) and 32 (42%) patients were classified into hypercoagulation and non-hypercoagulation groups, respectively. The hypercoagulation group showed elevated CA125 and CEA levels, no history of hypertension, and pancreatic cancer more frequently, and higher CRP values, lower hemoglobin values, longer prothrombin time and lower platelet counts than the non-hypercoagulation group. In multivariable analysis, only elevation of CA125 was independently associated with the hypercoagulation group (adjusted odds ratio: 5.59 [95% confidence interval]: 1.33-26.41). CONCLUSIONS: CA125, a tumor marker for mucin-producing tumors, was related to stroke due to cancer- associated hypercoagulation. CA125 may be a potential biomarker for cancer-associated hypercoagulation.

[A Case of Chemotherapy with Low-Dose Paclitaxel and Bevacizumab for Elderly Recurrent Breast Cancer Patient].

An 86-year-old woman underwent mastectomy with sentinel lymph node biopsy for cStage ⅡA breast cancer. The subtype of tumor was triple negative breast cancer. Pulmonary metastasis was found 1 month after surgery. Chemotherapy was done because of her good performance status(PS)and her hope. Administration of S-1 produced SD status of tumor for 8 months. However, NCC-ST-439 was increased and tumor size was enlarged. Therefore, the second line of chemotherapy by low-dose- biweekly paclitaxel and bevacizumab was planned because of her high age and good PS. Thereafter, tumor maker levels dramatically decreased and lung metastasis turned to be small. This therapy had been continued without any severe adverse events for 9 months. Unfortunately, this therapy was failed because of proteinuria, but pulmonary metastasis kept favorable efficacy during administration. Biweekly low-dose paclitaxel and bevacizumab therapy can be safe and effective therapy even for elderly patient with recurrent and metastatic breast cancer.

Characterizing fine-root traits by species phylogeny and microbial symbiosis in 11 co-existing woody species.

Understanding the differences in fine-root traits among different species is essential to gain a detailed understanding of resource conservation and acquisition strategies of plants. We aimed to explore whether certain root traits are consistent among subsets of species and characterize species together into meaningful community groups. We selected 11 woody species from different microbial symbiotic groups (ectomycorrhiza, arbuscular mycorrhiza, and rhizobia) and phylogenetic groups (broad-leaved angiosperms and coniferous gymnosperms) from the cool temperate forests of Nagano, Japan. We measured root architectural (branching intensity), morphological (root tissue density and specific root length), chemical (N and K concentrations), and anatomical (total stele and total cortex) traits. Significant differences were observed in all root traits, although many species did not differ from one another. Branching intensity was found to be the greatest variation in the measured root traits across the 11 woody species. The results of a principal component analysis of root traits showed a distinct separation between angiosperms and gymnosperms. We identified clusters of species based on their multidimensional root traits that were consistent with the different phylogenetic microbial association groups. Gymnosperm roots may be more resource conservative, while angiosperm roots may be more acquisitive for water and nutrients. We consider that the advances in root traits combination will make a breakthrough in our ability to differentiate the community groups rather than individual root trait.

Clinical and Radiological Characteristics of Intracranial Artery Dissection Using Recently Proposed Diagnostic Criteria.

BACKGROUND: Data on the clinical and radiological characteristics of intracranial artery dissection (IAD) have remained limited. Our purpose was to reveal the clinical and radiological characteristics of IAD according to diagnostic criteria for IAD as recently reported by a group of international experts. METHODS: Patients were retrospectively enrolled using a prospective single-center stroke registry between 2011 and 2016. Baseline characteristics and radiological findings including conventional magnetic resonance imaging (MRI) sequences, magnetic resonance angiography (MRA), high-resolution 3-dimensional T1-weighted imaging (HR-3D-T1WI), and digital subtraction angiography were reviewed. We performed statistical comparisons to determine which findings from which modalities are useful. RESULTS: We identified 118 patients with suspected artery dissection, with 64 patients (median age, 51 [interquartile range, 45-56) years; 16 women) finally meeting the criteria for definite (n = 47), probable (n = 15), or possible (n = 2) idiopathic IAD. Ischemic stroke alone was found in 31 patients (48%) on admission. There were 36 patients (56%) suffering from hypertension and 39 (61%) with smoking history. The vertebral artery alone was the most affected in 42 patients (66%). Intramural hematoma (IMH) was more frequently detected on HR-3D-T1WI than on conventional MRI/MRA (odds ratio, 4.72; 95% confidence interval, 1.71-13.00). In 54 patients (84%), the modified Rankin Scale score after 3 months was 0-1. CONCLUSIONS: Male dominance and age at IAD onset were similar to previous studies, and more than half had hypertension and smoking history. We confirmed that HR-3D-T1WI is useful for detecting IMH in the diagnostic criteria.

Detection of Stenosis Progression in Intracranial Vertebral Artery Dissection Using Carotid Ultrasonography.

BACKGROUND: The purpose of this study was to assess whether carotid ultrasonography indices detect arterial stenosis progression in patients with vertebral artery (VA) dissection. METHODS: This was a retrospective, single-center, observational study that enrolled patients with intracranial VA dissection who were admitted from January 2011 to June 2017. Magnetic resonance angiography (MRA) was done on admission and followed up at a median 20 days after onset (interquartile range [IQR] 9-58 days), and ultrasonography was performed at a median of 22 (interquartile range 7-56) days. Peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), and pulsatility index (PI) were measured by ultrasonography, and the ratio of each follow-up value to the baseline (follow-up/baseline) value was calculated. Two stroke neurologists categorized into 3 groups by morphological changes of the dissected vessel: patients with stenosis progression (progression group: P-group); those with no remarkable change or dilatation improved (stable group: S-group); and those with stenosis regression or dilatation enlargement (enlargement group: E-group). Ultrasonography indices were compared among the groups. RESULTS: Of the 42 patients who were enrolled to this study, 39 patients underwent ultrasonography and MRA on both admission and follow-up. The PI ratio was significantly higher in the P-group than in the S-group (1.96 ± .80 versus .98 ± .44, P = .02) and in the E-group (versus .65 ± .35, P < .01). There were no significant differences in the PSV ratio, EDV ratio, and MV ratio. CONCLUSIONS: In patients with VA dissection, the PI ratio on ultrasonography is a promising index to detect stenosis progression.

Cancer-Associated Hypercoagulation Increases the Risk of Early Recurrent Stroke in Patients with Active Cancer.

BACKGROUND: This study assessed the incidence and predictors of short-term stroke recurrence in ischemic stroke patients with active cancer, and elucidated whether cancer-associated hypercoagulation is related to early recurrent stroke. METHODS: We retrospectively enrolled acute ischemic stroke patients with active cancer admitted to our hospital between 2006 and 2017. Active cancer was defined as diagnosis or treatment for any cancer within 12 months before stroke onset, known recurrent cancer or metastatic disease. The primary clinical outcome was recurrent ischemic stroke within 30 days. RESULTS: One hundred ten acute ischemic stroke patients with active cancer (73 men, age 71.3 ± 10.1 years) were enrolled. Of those, recurrent stroke occurred in 12 patients (11%). When patients with and without recurrent stroke were compared, it was found that those with recurrent stroke had a higher incidence of pancreatic cancer (33 vs. 10%), systemic metastasis (75 vs. 39%), multiple vascular territory infarctions (MVTI; 83 vs. 40%), and higher -D-dimer levels (16.9 vs. 2.9 µg/mL). Multivariable logistic regression analysis showed that each factor mentioned above was not significantly associated with stroke recurrence independently, but high D-dimer (hDD) levels (≥10.4 µg/mL) and MVTI together were significantly associated with stroke recurrence (OR 6.20, 95% CI 1.42-30.7, p = 0.015). CONCLUSIONS: Ischemic stroke patients with active cancer faced a high risk of early recurrent stroke. The concurrence of hDD levels (≥10.4 µg/mL) and MVTI was an independent predictor of early recurrent stroke in active cancer patients. Our findings suggest that cancer-associated hypercoagulation increases the early recurrent stroke risk.

Urgent Detection of Acute Type A Aortic Dissection in Hyperacute Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Urgent diagnosis of acute Stanford type A aortic dissection (AAD) in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) is sometimes challenging. We assessed predictive values for markers of AAD in patients with AIS or TIA. METHODS: Consecutive patients with AIS or TIA with AAD who presented to our emergency room within 4.5 hours of symptom onset between 2007 and 2014 were compared with patients without AAD seen between 2012 and 2014. RESULTS: Data were obtained for 24 patients with AIS or TIA with AAD (15 women; mean age, 75 ± 12 years) and 812 patients without AAD (305 women; mean age, 73 ± 12 years). Compared with patients without AAD, patients with AAD displayed significantly higher systolic blood pressure (SBP) laterality (30 ± 20 mm Hg versus 12 ± 11 mm Hg), initial D-dimer concentration (median 38.1 µg/mL versus 1.3 µg/mL), and mediastinal width-to-chest width (M/C) ratio on x-ray (.35 ± .05 versus .29 ± .05), and more frequently showed common carotid artery (CCA) dissection on carotid ultrasonography (84% versus 1%) and pericardial effusion on echocardiography (43% versus 0%). Sensitivity and specificity to identify AAD were 80% and 75% for SBP laterality 17 mm Hg or greater; 100% and 86% for D-dimer concentration 4.1 µg/mL or greater; 75% and 76% for M/C ratio .32 or greater; 84% and 99% for CCA dissection; and 43% and 100% for pericardial effusion, respectively. CONCLUSIONS: High D-dimer level may provide the most reliable screening test for AAD in patients with AIS or TIA. CCA dissection on ultrasonography appears to represent the most disease-specific finding and shows acceptable sensitivity.

Myasthenic symptoms in anti-low-density lipoprotein receptor-related protein 4 antibody-seropositive amyotrophic lateral sclerosis: two case reports.

BACKGROUND: Myasthenic symptoms can be present in patients with amyotrophic lateral sclerosis (ALS). These symptoms have been considered to be caused by the degeneration of distal motor neurons and the neuromuscular junction (NMJ). Recent studies suggested that antibody to low-density lipoprotein receptor-related protein 4 (LRP4) was a pathogenic agent of myasthenia gravis (MG), and it was also detected in ALS patients. CASE PRESENTATION: Patient 1: A 58-year-old Japanese man developed progressive weakness and subsequent myasthenic symptoms including oculomotor disturbance. Clinical examination and electrophysiological studies confirmed upper and lower motor neuron involvement and NMJ dysfunction, and anti-LRP4 antibody was detected in his serum. A series of immunotherapies, including steroid pulse therapy, intravenous immunoglobulin, and plasmapheresis, was performed, and the myasthenic symptoms partially improved. The titer of anti-LRP4 antibody subsequently decreased. However, the therapeutic effect was transient, and ALS symptoms progressed. His clinical findings fulfilled the criteria of probable ALS using the Awaji criteria. Patient 2: A 74-year-old Japanese man suffered from progressive weakness of all limbs and dropped head in the evening. He complained of diplopia with a lateral horizontal gaze. Probable ALS was diagnosed because of the upper and lower motor neuron signs, whereas anti-LRP4 antibody was detected. Several immunotherapies were administered, and the myasthenic symptoms partially responded to each therapy. However, the truncal muscle weakness progressed, and he died of respiratory failure. CONCLUSION: We report two anti-LRP4 antibody-seropositive ALS patients with myasthenia who were not typical of ALS patients, and showed partial responses to immunotherapies. The anti-LRP4 antibody-seropositive status may influence developing ALS and cause additional ALS symptoms.

[A Case of Multiple Bevacizumab-Related Colonic Perforations during Opioid Use].

We present the case ofa 54-year-old man who had been treated with bevacizumab-containing chemotherapy for a postoperative recurrence of lung cancer for 5 months; he had used opioids for cancer pain in his right lateral chest for 2 months. He was admitted to the hospital because his chest pain had worsened 5 days earlier and he was experiencing a dull pain in his lower abdomen. His condition was recognized as an aggravation of the cancer pain and his opioid dose was increased. He presented with intense abdominal pain 6 days after admission, and we diagnosed gastrointestinal perforations from an abdominal CT scan. Therefore, we undertook an emergency operation. Multiple perforations were seen on the transverse and descending colon; an extensive colectomy and a colostomy were performed. Histopathological findings showed that multiple ulcer perforations and normal mucosa coexisted throughout the resected specimen. Bevacizumab-induced ischemic changes were the suspected cause. When pain control becomes variable during opioid use, conditions such as bevacizumab-related gastrointestinal perforations should be considered, in addition to progression of the cancer pain itself, and the appropriate treatment should be administered.

Intraspecific variation in fine root respiration and morphology in response to in situ soil nitrogen fertility in a 100-year-old Chamaecyparis obtusa forest.

Soil N fertility has an effect on belowground C allocation, but the physiological and morphological responses of individual fine root segments to variations in N availability under field conditions are still unclear. In this study, the direction and magnitude of the physiological and morphological function of fine roots in response to variable in situ soil N fertility in a forest site were determined. We measured the specific root respiration (Rr) rate, N concentration and morphology of fine root segments with 1-3 branching orders in a 100-year-old coniferous forest of Chamaecyparis obtusa. Higher soil N fertility induced higher Rr rates, root N concentration, and specific root length (SRL), and lower root tissue density (RTD). In all fertility levels, the Rr rates were significantly correlated positively with root N and SRL and negatively with RTD. The regression slopes of respiration with root N and RTD were significantly higher along the soil N fertility gradient. Although no differences in the slopes of Rr and SRL relationship were found across the levels, there were significant shifts in the intercept along the common slope. These results suggest that a contrasting pattern in intraspecific relationships between specific Rr and N, RTD, and SRL exists among soils with different N fertility. Consequently, substantial increases in soil N fertility would exert positive effects on organ-scale root performance by covarying the Rr, root N, and morphology for their potential nutrient and water uptake.

[Examination of outcomes after conversion surgery for Stage IVGastric cancer in our hospital].

PURPOSE: We examined the outcomes of conversion surgery (CS) for Stage IV gastric cancer performed in our hospital. OBJECTIVE AND METHOD: We retrospectively examined the outcomes of 5 Stage IV gastric cancer patients, for whom surgical excision was possible and CS was performed after induction chemotherapy between January 2010 and December 2013. RESULTS: The median age of the patients who underwent CS was 62 years, and non-recovering factors were as follows: M1 (LYM) for 3 patients, H1 for 1 patient, and P1 for 1 patient. For all patients, the induction chemotherapy regimen consisted only of TS-1+cisplatin (CDDP). Using diagnostic imaging to determine treatment effect, we found that 2 patients showed a partial response(PR)as a result of the induction chemotherapy. As a result of CS, R0 surgery could be enforced to 3 cases and postoperative complications accepted neither. Ef-grade which of the histopathological judging of the chemotherapy were 1a: 4 cases, 2: 1 case. After adjuvant chemotherapy treatment in 3 patients, the median survival time (MST) of the CS patients was 22.5 months. In contrast, the MST of non-CS patients, who received treatments other than CS, was 4 months. These results indicate that the MST for CS patients was substantially longer compared to patients who did not receive CS (p=0.046). CONCLUSION: Although CS in response to Stage IV gastric cancer fully needed to examine selection of a case, the timing of operation introduction, etc. to be successful, a possibility of contributing to a prognosis improvement in a multidisciplinary treatment was suggested.

The relationship between neurological worsening and lesion patterns in patients with acute middle cerebral artery stenosis.

BACKGROUND: Intracranial atherosclerotic disease is one of the most common causes of ischemic stroke especially in Asians, Hispanics and blacks. Although middle cerebral artery (MCA) stenosis is increasingly being recognized with the advent of magnetic resonance angiography (MRA) or transcranial Doppler ultrasonography, few studies have focused on acute neurological worsening (NW) in patients with MCA stenosis. We investigated the relationship between NW and lesion patterns detected by diffusion-weighted imaging (DWI). METHODS: We studied 44 consecutive patients out of a total of 2,863 consecutive patients who had symptomatic lesions in the territory of the MCA and in whom MRA and/or conventional angiography showed isolated MCA stenosis ≥50% in the MCA trunk. Acute DWI lesion patterns were classified as follows: (1) pial artery territory infarcts (PAI); (2) small cortical and/or subcortical infarcts (SCS); (3) deep penetrating artery territory infarcts (DPI); (4) cortical border zone infarcts (CBZ), and (5) internal border zone infarcts (IBZ). NW was defined as worsening by ≥2 points on the National Institutes of Health Stroke Scale (NIHSS) during the first 7 days. Functional outcome was assessed by the modified Rankin Scale (mRS) at 3 months after stroke onset. Poor outcome was defined as ≥3 on the mRS. The severity of MCA stenosis on MRA was further categorized as 50-75% (moderate) and >75% or focal signal loss with the presence of distal MCA signal (severe). RESULTS: There were 14 patients (31.8%) who showed NW and 16 patients (36.3%) who showed poor outcomes. Nine of the 14 patients with NW showed poor outcomes (64.2%). The most frequent lesions in the present study were SCS (n = 16, 36.3%), followed by IBZ (n = 12, 27.2%) and DPI (n = 11, 25.0%). Prevalence of IBZ was significantly higher in the group with NW compared to that without NW (p = 0.0081), while the prevalence of SCS, DPI, PAI and CBZ did not differ between the two groups. Logistic regression analysis showed significantly high age- and sex-adjusted odds ratios (ORs) for NW only for IBZ (OR 10.9, p = 0.0051). The degree of stenosis did not correlate with NW and lesion patterns. CONCLUSIONS: Only IBZ among various lesion patterns correlated strongly with NW. IBZ are considered to be more associated with hemodynamic compromise, while embolic pathogeneses contribute more to CBZ or SCS. Early interventional medical treatments such as thrombolytic or anti-platelet therapy or stenting should be considered in cases of IBZ in MCA stenosis.

Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals.

Short interfering RNA (siRNA) is a potent activator of the mammalian innate immune system. When considering possible clinical applications of siRNA for humans, the adverse immunostimulatory effects must also be taken into account. Here, we show that atelocollagen-mediated systemic delivery of siRNA without chemical modifications did not cause any immunostimulation in both animals and human peripheral blood mononuclear cells (PBMCs), even if the siRNA harbored an interferon (IFN)-inducible sequence. In contrast, systemic delivery of immunostimulatory RNA (isRNA)-mediated by a cationic lipid (such as Invivofectamine) induced potent type-I IFNs and inflammatory cytokines. Regarding the mechanism by which the isRNA/atelocollagen complex avoided adverse effects on immunostimulation, we revealed that this complex was not incorporated into PBMCs. On the other hand, Invivofectamine delivered isRNA into PBMCs. The use of either atelocollagen or Invivofectamine as a vehicle elicited significant and undistinguishable therapeutic effects in a contact hypersensitivity (CHS) inflammatory model mouse, when we intravenously injected the siRNA targeting monocyte chemoattractant protein-1 as the complex. For the goal of realizing siRNA-based medicines for humans, atelocollagen is an excellent and promising delivery vehicle, and it has the useful advantage of evading detection by the "radar" of innate immunity.

[Protocol for the administration of modified FOLFOX6 (mFOLFOX6) in patients with unresectable/recurrent colorectal cancer].

In patients undergoing FOLFOX6 therapy for the treatment of unresectable/recurrent colorectal cancer, control of cumulative peripheral neuropathy is problematic. In our department, we stop using mFOLFOX6 as a primary therapy after 6 to 8 courses. Instead, we use mFOLFOX6 as a secondary therapy, and re-introduce mFOLFOX6 as a tertiary therapy; the patients undergoing this treatment protocol were included in Group A. We have studied the degree of neurotoxicity and the time of its occurrence in these patients compared to those undergoing the standard method (Group B; 12 cases). Grade 3 peripheral neuropathy was observed in both the groups. In Group B, peripheral neuropathy occurred in the primary treatment period, whereas in Group A, it appeared in the tertiary treatment period. Moreover, in Group A, we observed Grade 2 peripheral neuropathy in the primary treatment period in 3 cases, but this was promptly resolved after the therapy was shifted to the secondary treatment period. The period with neurological toxicities was shorter in Group A compared to Group B. When treating colorectal cancer with chemotherapy, it is important to elucidate how the prognosis can be improved while maintaining the quality of life( QOL). In our department, we place a greater emphasis on the QOL of the patient.

Poly(2-oxazoline)-Based Polyplexes as a PEG-Free Plasmid DNA Delivery Platform.

The present study expands the versatility of cationic poly(2-oxazoline) (POx) copolymers as a polyethylene glycol (PEG)-free platform for gene delivery to immune cells, such as monocytes and macrophages. Several block copolymers are developed by varying nonionic hydrophilic blocks (poly(2-methyl-2-oxazoline) (pMeOx) or poly(2-ethyl-2-oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2-isopropyl-2-oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2-methoxy-carboxyethyl-2-oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2-aminoethyl)amine (TREN). For the attachment of a targeting ligand, mannose, azide-alkyne cycloaddition click chemistry methods are employed. Of the two cationic side chains, polyplexes made with DET-containing copolymers transfect macrophages significantly better than those made with TREN-based copolymer. Likewise, nontargeted pEtOx-based diblock copolymer is more active in cell transfection than pMeOx-based copolymer. The triblock copolymer with hydrophobic block iPrOx performs poorly compared to the diblock copolymer which lacks this additional block. Surprisingly, attachment of a mannose ligand to either copolymer is inhibitory for transfection. Despite similarities in size and design, mannosylated polyplexes result in lower cell internalization compared to nonmannosylated polyplexes. Thus, PEG-free, nontargeted DET-, and pEtOx-based diblock copolymer outperforms other studied structures in the transfection of macrophages and displays transfection levels comparable to GeneJuice, a commercial nonlipid transfection reagent.

Recurrence of intracranial artery dissection more than a half year after the initial event.

INTRODUCTION: The management of intracranial artery dissection (IAD) has not been established, partly because the long-term course of the disease is not well-known. We retrospectively investigated the long-term course of IAD without subarachnoid hemorrhage (SAH) as an initial clinical presentation. METHODS: Of 147 consecutive spontaneous first-ever IAD patients hospitalized between March 2011 and July 2018, 44 with SAH were excluded, and the remaining 103 were investigated. We divided the patients into two groups: Recurrence group as those with recurrent intracranial dissection >1 month after the initial dissection, and Non-recurrence group as those without them. Clinical characteristics were compared between those two groups. RESULTS: The mean follow-up period was 33 months from the initial event. Recurrent dissection occurred in 4 patients (3.9%) >7 months after the initial dissection, none of whom were on antithrombotic treatments at recurrence. Three had ischemic stroke and the other had local symptoms [range: 8 to 44 months]. Nine (8.7%) had an ischemic stroke within 1 month of the initial event. There was no recurrent dissection between 1 and 7 months after the initial event. There was no significant difference in baseline characteristics between Recurrence and Non-recurrence groups. CONCLUSIONS: Four out of the 103 (3.9%) IAD patients had recurrent IAD >7 months after the initial event. IAD patients should be followed up for more than a half year after the initial event, with consideration given to the recurrence of IAD. Further research is needed on recurrence prevention measures to IAD patients.