[Four Cases Who Experienced Extravasation of Anthracyclines and Had Dexrazoxane Therapy].

We analyzed 4 cases who experienced extravasation of anthracyclines and had dexrazoxane therapy in our hospital. Concerned drugs were 2 adriamycin and 2 amrubicin cases and all cases received steroid ointment therapy, and no cases showed severe condition such as skin ulcer. As dexrazoxane is known to enhance bone marrow suppression of anti-cancer drugs, the nadir of neutropenia and thrombocytopenia was observed from day 10 to 17 in our cases. We made a domestic manual and have used in various professionals. Dexrazoxane would contribute to the reduction of skin damage due to extravasation if we could manage bone marrow suppression successfully.

Correlation between antibiotic use and antibiotic resistance: A multicenter study using the Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system in Hokkaido, Japan.

BACKGROUND: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan. METHODS: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro. RESULTS: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P < .001), and ρ = 0.502 (P = .029), respectively]. CONCLUSIONS: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures.

Enteral lorlatinib after alectinib as a treatment option in anaplastic lymphoma kinase-positive non-small cell lung cancer with triple problems: carcinomatous meningitis, poor performance status, and dysphagia-a case report.

Alectinib treatment is effective in patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC; hereafter ALK-positive NSCLC) who exhibit central nervous system (CNS) relapse and poor performance status (PS). Lorlatinib treatment is effective upon failure of other ALK inhibitor-based treatments. However, much remains unknown about the efficacy of lorlatinib in patients with ALK-positive NSCLC, who have triple problems, carcinomatous meningitis, poor PS, and dysphagia, after alectinib treatment. Here, we report the remarkable response of a 73-year-old patient with ALK-positive NSCLC showing carcinomatous meningitis due to CNS metastases, poor PS, and dysphagia to lorlatinib. Lorlatinib administration through a nasogastric tube alleviated complications related to consciousness within three days, and the patient survived for 16 months after CNS relapse. Lorlatinib could be a treatment option for patients with ALK-positive NSCLC showing carcinomatous meningitis, poor PS, and dysphagia upon failure of other ALK inhibitor-based treatments.

Selective E to Z isomerization of 1,3-Dienes Enabled by A Dinuclear Mechanism.

The E/Z stereocontrol in a C=C bond is a fundamental issue in olefin synthesis. Although the thermodynamically more stable E geometry is readily addressable by thermal Z to E geometric isomerization through equilibrium, it has remained difficult to undergo thermal geometric isomerization to the reverse E to Z direction in a selective manner, because it requires kinetic trapping of Z-isomer with injection of chemical energy. Here we report that a dinuclear PdI-PdI complex mediates selective isomerization of E-1,3-diene to its Z-isomer without photoirradiation, where kinetic trapping is achieved through rational sequences of dinuclear elementary steps. The chemical energy required for the E to Z isomerization can be injected from an organic conjugate reaction through sharing of common Pd species.

Evaluation for pharmacokinetic exposure of cytotoxic anticancer drugs in elderly patients receiving (R-)CHOP therapy.

(R-)miniCHOP therapy, which delivers approximately half-doses of the (R-)CHOP regimen, has shown efficacy and safety in patients who are more than 80 years old. This study aimed to compare the area under the plasma concentration-time curves (AUCs) of vincristine (VCR), doxorubicin (DXR), and cyclophosphamide (CPA) between (R-)CHOP and (R-)miniCHOP regimens. The AUCs were compared between patients aged 65-79 years receiving (R-)CHOP therapy and those aged 80 years and older receiving (R-)miniCHOP therapy. Age was not an independent variable for predicting the dose-adjusted AUCs (AUC/Ds) of cytotoxic anticancer drugs. The median AUCs of DXR and CPA were significantly smaller in the (R-)miniCHOP group than in the (R-)CHOP group (168.7 vs. 257.9 ng h/mL, P = 0.003, and 219.9 vs. 301.7 µg h/mL, P = 0.020, respectively). The median AUCs of VCR showed the same trend but the difference was not significant (24.83 vs. 34.85 ng h/mL, P = 0.135). It is possible that the AUCs of VCR, DXR, and CPA in patients aged 80 years and older receiving (R-)miniCHOP therapy may be lower than those in patients 65-79 years old receiving (R-)CHOP therapy.

Evaluation of the diameter of the distal radial artery at the anatomical snuff box using ultrasound in Japanese patients.

Catheter angioplasty or angiography via the distal access point of the radial artery (dRA), located at the anatomical snuff box, is a less invasive strategy for coronary intervention attracting considerable attention. Determining the diameter of the dRA is necessary to minimize the risk of artery occlusion and safely perform catheter intervention. This was a retrospective observational study including patients who underwent coronary angiography or coronary intervention at Aomori Kyoritsu Hospital, Aomori, Japan, between February 2018 and August 2018. The diameter of the dRA and the conventional access point of the radial artery (cRA) at the wrist of the patients were measured using ultrasound prior to angiography or interventional procedure. A total of 120 patients were analyzed. In male patients, the diameters of the cRA and dRA were 2.62 ± 0.60 mm and 2.04 ± 0.43 mm, respectively. In females, these diameters were 2.44 ± 0.51 mm and 1.96 ± 0.44 mm, respectively. Overall, the dRA was statistically significantly smaller than the cRA. However, variations were observed, with eight patients (6.7%) having a larger dRA than cRA. The diameter of the dRA indicated only that of the cRA. A multivariate analysis did not reveal factors associated with vessel diameter. The size and anatomy of the dRA varied considerably. Thus, it is difficult to predict the actual diameter of the artery. Customized selection of the size of the sheath and site of intervention is essential for each patient to safely perform ultrasound examination prior to cannulation.

Synthesis and Evaluation as a Blood-Brain Barrier-Permeable Probe of 7-N-(PROXYL-3-yl-methyl)theophylline.

The drug-nitroxide radical hybrid-compound 7-N-((2,2,5,5-tetramethylpyrrolidine-1-yloxy(PROXYL))-3-yl-methyl)theophylline (3) was synthesized by coupling 7-N-tosyltheophylline with 3-hydroxymethyl-PROXYL, HMP). The stability of 3 relative to that of HMP was examined in the presence of the anti-oxidant, ascorbic acid (AsA). The initial reduction rate constants of 3 and HMP were 11.9±5.3 and 6.1±5.2 M-1 min-1, respectively. In the presence of glutathione (GSH), these constants increased slightly to 22.3±6.8 and 9.1±2.4 M-1 min-1, respectively. Two-dimensional cranial electron paramagnetic resonance imaging of mice intravenously injected with 3 via the tail vein revealed that probe 3 enters the mouse brain by passing through the blood-brain barrier (BBB).

Six underlying health conditions strongly influence mortality based on pneumonia severity in an ageing population of Japan: a prospective cohort study.

BACKGROUND: Mortality prediction of pneumonia by severity scores in patients with multiple underlying health conditions has not fully been investigated. This prospective cohort study is to identify mortality-associated underlying health conditions and to analyse their influence on severity-based pneumonia mortality prediction. METHODS: Adult patients with community-acquired pneumonia or healthcare-associated pneumonia (HCAP) who visited four community hospitals between September 2011 and January 2013 were enrolled. Candidate underlying health conditions, including demographic and clinical characteristics, were incorporated into the logistic regression models, along with CURB (confusion, elevated urea nitrogen, tachypnoea, and hypotension) score as a measure of disease severity. The areas under the receiver operating characteristic curves (AUROC) of the predictive index based on significant underlying health conditions was compared to that of CURB65 (CURB and age ≥ 65) score or Pneumonia severity index (PSI). Mortality association between disease severity and the number of underlying health conditions was analysed. RESULTS: In total 1772 patients were eligible for analysis, of which 140 (7.9%) died within 30 days. Six underlying health conditions were independently associated: home care (adjusted odds ratio, 5.84; 95% confidence interval, CI, 2.28-14.99), recent hospitalization (2.21; 1.36-3.60), age ≥ 85 years (2.15; 1.08-4.28), low body mass index (1.99, 1.25-3.16), neoplastic disease (1.82; 1.17-2.85), and male gender (1.78; 1.16-2.75). The predictive index based on these conditions alone had a significantly or marginally higher AUROC than that based on CURB65 score (0.78 vs 0.66, p = 0.02) or PSI (0.78 vs 0.71, p = 0.05), respectively. Compared to this index, the AUROC of the total score consisting of six underlying health conditions and CURB score (range 0-10) did not improve mortality predictions (p = 0.3). In patients with one or less underlying health conditions, the mortality was discretely associated with severe pneumonia (CURB65 ≥ 3) (risk ratio: 7.24, 95%CI: 3.08-25.13), whereas in patients with 2 or more underlying health conditions, the mortality association with severe pneumonia was not detected (risk ratio: 1.53, 95% CI: 0.94-2.50). CONCLUSIONS: Mortality prediction based on pneumonia severity scores is highly influenced by the accumulating number of underlying health conditions in an ageing society. The validation using a different cohort is necessary to generalise the conclusion.

Synthesis and Reduction Kinetics of Five Ibuprofen-Nitroxides for Ascorbic Acid and Methyl Radicals.

The hybrid compounds 1-5 comprised of five nitroxides with ibuprofen were synthesized and their reduction rate for ascorbic acid (AsA) and methyl radicals were measured in comparison with 3-hydroxy-tetramethylpyrrolidine-1-oxyl (PROXYL) 6. The rate constants in reduction reaction with 200-fold excess of AsA were determined in following order: 1 (0.42±0.06), 3 (0.17±0.06), 2 (0.10±0.05), and 6 (0.09±0.02 M-1s-1). The remaining two sterically shielded nitroxides 4 and 5 scarcely reacted with AsA. In the reaction with the more reactive methyl radicals, produced by 200-fold excess of Fenton's reagent, the reduction rates of 2, 4, and 5 were in the following decreasing order: 2 (1.1±0.2), 4 (0.76±0.09), and 5 (0.31±0.03 M-1s-1).

Effects of generalized pooling on binocular disparity selectivity of neurons in the early visual cortex.

The key problem of stereoscopic vision is traditionally defined as accurately finding the positional shifts of corresponding object features between left and right images. Here, we demonstrate that the problem must be considered in a four-dimensional parameter space; with respect not only to shifts in space (X, Y), but also spatial frequency (SF) and orientation (OR). The proposed model sums outputs of binocular energy units linearly over the multi-dimensional V1 parameter space (X, Y, SF, OR). Theoretical analyses and physiological experiments show that many binocular neurons achieve sharp binocular tuning properties by pooling the output of multiple neurons with relatively broad tuning. Pooling in the space domain sharpens disparity-selective responses in the SF domain so that the responses to combinations of unmatched left-right SFs are attenuated. Conversely, pooling in the SF domain sharpens disparity selectivity in the space domain, reducing the possibility of false matches. Analogous effects are observed for the OR domain in that the spatial pooling sharpens the binocular tuning in the OR domain. Such neurons become selective to relative OR disparity. Therefore, pooling allows the visual system to refine binocular information into a form more desirable for stereopsis.This article is part of the themed issue 'Vision in our three-dimensional world'.

Subspace mapping of the three-dimensional spectral receptive field of macaque MT neurons.

Neurons in the middle temporal (MT) visual area are thought to represent the velocity (direction and speed) of motion. Previous studies suggest the importance of both excitation and suppression for creating velocity representation in MT; however, details of the organization of excitation and suppression at the MT stage are not understood fully. In this article, we examine how excitatory and suppressive inputs are pooled in individual MT neurons by measuring their receptive fields in a three-dimensional (3-D) spatiotemporal frequency domain. We recorded the activity of single MT neurons from anesthetized macaque monkeys. To achieve both quality and resolution of the receptive field estimations, we applied a subspace reverse correlation technique in which a stimulus sequence of superimposed multiple drifting gratings was cross-correlated with the spiking activity of neurons. Excitatory responses tended to be organized in a manner representing a specific velocity independent of the spatial pattern of the stimuli. Conversely, suppressive responses tended to be distributed broadly over the 3-D frequency domain, supporting a hypothesis of response normalization. Despite the nonspecific distributed profile, the total summed strength of suppression was comparable to that of excitation in many MT neurons. Furthermore, suppressive responses reduced the bandwidth of velocity tuning, indicating that suppression improves the reliability of velocity representation. Our results suggest that both well-organized excitatory inputs and broad suppressive inputs contribute significantly to the invariant and reliable representation of velocity in MT.

Supranormal orientation selectivity of visual neurons in orientation-restricted animals.

Altered sensory experience in early life often leads to remarkable adaptations so that humans and animals can make the best use of the available information in a particular environment. By restricting visual input to a limited range of orientations in young animals, this investigation shows that stimulus selectivity, e.g., the sharpness of tuning of single neurons in the primary visual cortex, is modified to match a particular environment. Specifically, neurons tuned to an experienced orientation in orientation-restricted animals show sharper orientation tuning than neurons in normal animals, whereas the opposite was true for neurons tuned to non-experienced orientations. This sharpened tuning appears to be due to elongated receptive fields. Our results demonstrate that restricted sensory experiences can sculpt the supranormal functions of single neurons tailored for a particular environment. The above findings, in addition to the minimal population response to orientations close to the experienced one, agree with the predictions of a sparse coding hypothesis in which information is represented efficiently by a small number of activated neurons. This suggests that early brain areas adopt an efficient strategy for coding information even when animals are raised in a severely limited visual environment where sensory inputs have an unnatural statistical structure.

Integration of Multiple Spatial Frequency Channels in Disparity-Sensitive Neurons in the Primary Visual Cortex.

For our vivid perception of a 3-D world, the stereoscopic function begins in our brain by detecting slight shifts of image features between the two eyes, called binocular disparity. The primary visual cortex is the first stage of this processing, and neurons there are tuned to a limited range of spatial frequencies (SFs). However, our visual world is generally highly complex, composed of numerous features at a variety of scales, thereby having broadband SF spectra. This means that binocular information signaled by individual neurons is highly incomplete, and combining information across multiple SF bands must be essential for the visual system to function in a robust and reliable manner. In this study, we investigated whether the integration of information from multiple SF channels begins in the cat primary visual cortex. We measured disparity-selective responses in the joint left-right SF domain using sequences of dichoptically flashed grating stimuli consisting of various combinations of SFs and phases. The obtained interaction map in the joint SF domain reflects the degree of integration across different SF channels. Our data are consistent with the idea that disparity information is combined from multiple SF channels in a substantial fraction of complex cells. Furthermore, for the majority of these neurons, the optimal disparity is matched across the SF bands. These results suggest that a highly specific SF integration process for disparity detection starts in the primary visual cortex. SIGNIFICANCE STATEMENT: Our visual world is broadband, containing features with a wide range of object scales. On the other hand, single neurons in the primary visual cortex are narrow-band, being tuned narrowly for a specific scale. For robust visual perception, narrow-band information of single neurons must be integrated eventually at some stage. We have examined whether such an integration process begins in the primary visual cortex with respect to binocular processing. The results suggest that a subset of cells appear to combine binocular information across multiple scales. Furthermore, for the majority of these neurons, an optimal parameter of binocular tuning is matched across multiple scales, suggesting the presence of a highly specific neural integration mechanism.

Complex cells in the cat striate cortex have multiple disparity detectors in the three-dimensional binocular receptive fields.

Along the visual pathway, neurons generally become more specialized for signaling a limited subset of stimulus attributes and become more invariant to changes in the stimulus position within the receptive fields (RFs). One of the likely mechanisms underlying such invariance appears to be pooling of detectors located at different positions. Does such spatial pooling occur for disparity-selective neurons in primary visual cortex? To examine whether the three-dimensional (3D) binocular RFs are constructed by pooling detectors for binocular disparity, we investigated binocular interactions in the 3D space for neurons in the cat striate cortex. Approximately one-third of complex cells showed the spatial pooling of disparity detectors to a significant degree, whereas the majority of simple cells did not. The degree of spatial pooling of disparity detectors along the preferred orientation axis was generally larger than that along the axis orthogonal to the orientation axis. We then reconstructed 3D binocular RFs in their complete form and examined their structures. Disparity tuning curves were compared across positions along the orientation axis in the RFs. A small population of cells appeared to show a gradual shift of the preferred disparity along this axis, indicating that they can potentially signal inclination in the 3D space. However, the majority of cells exhibited a position-invariant disparity tuning. Finally, disparity tuning curves were examined for all oblique angles in addition to horizontal and vertical. Tunings were broadest along the orientation axis as the disparity energy model predicts.

Internal spatial organization of receptive fields of complex cells in the early visual cortex.

The receptive fields of complex cells in the early visual cortex are economically modeled by combining outputs of a quadrature pair of linear filters. For actual complex cells, such a minimal model may be insufficient because many more simple cells are thought to make up a complex cell receptive field. To examine the minimalist model physiologically, we analyzed spatial relationships between the internal structure (subunits) and the overall receptive fields of individual complex cells by a two-stimulus interaction technique. The receptive fields of complex cells are more circular and only slightly larger than their subunits in size. In addition, complex cell subunits occupy spatial extents similar to those of simple cell receptive fields. Therefore in these respects, the minimalist schema is a fair approximation to actual complex cells. However, there are violations against the minimal model. Simple cell receptive fields have significantly fewer subregions than complex cell subunits and, in general, simple cell receptive fields are elongated more horizontally than vertically. This bias is absent in complex cell subunits and receptive fields. Thus simple cells cannot be equated to individual complex cell subunits and spatial pooling of simple cells may occur anisotropically to constitute a complex cell subunit. Moreover, when linear filters for complex cell subunits are examined separately for bright and dark responses, there are significant imbalances and position displacements between them. This suggests that actual complex cell receptive fields are constructed by a richer combination of linear filters than proposed by the minimalist model.