Impact of early initiation of renin-angiotensin blockade on renal function and clinical outcomes in patients with hypertensive emergency: a retrospective cohort study.

BACKGROUND: Hypertensive emergency is a critical disease that causes multifaceted sequelae, including end-stage kidney disease and cardiovascular disease. Although the renin-angiotensin-aldosterone (RAA) system is enormously activated in this disease, there are few reports that attempt to characterize the effect of early use of RAA inhibitors (RASi) on the temporal course of kidney function. METHODS: This retrospective cohort study was conducted to clarify whether the early use of RASi during hospitalization offered more favorable benefits on short-term renal function and long-term renal outcomes in patients with hypertensive emergencies. We enrolled a total of 49 patients who visited our medical center with acute severe hypertension and multiple organ dysfunction between April 2012 and August 2020. Upon admission, the patients were treated with intravenous followed by oral antihypertensive drugs, including RASi and Ca channel blockers (CCB). Kidney function as well as other laboratory and clinical parameters were compared between RASi-treated and CCB- treated group over 2 years. RESULTS: Antihypertensive treatment effectively reduced blood pressure from 222 ± 28/142 ± 21 to 141 ± 18/87 ± 14 mmHg at 2 weeks and eGFR was gradually restored from 33.2 ± 23.3 to 40.4 ± 22.5 mL/min/1.73m2 at 1 year. The renal effect of antihypertensive drugs was particularly conspicuous when RASi was started in combination with other conventional antihypertensive drugs at the early period of hospitalization (2nd day [IQR: 1-5.5]) and even in patients with moderately to severely diminished eGFR (< 30 mL/min/1.73 m2) on admission. In contrast, CCB modestly restored eGFR during the observation period. Furthermore, renal survival probabilities were progressively deteriorated in patients who had manifested reduced eGFR (< 15 mL/min/1.73 m2) or massive proteinuria (urine protein/creatinine ≥ 3.5 g/gCr) on admission. Early use of RASi was associated with a favorable 2-year renal survival probability (0.90 [95%CI: 0.77-1.0] vs. 0.63 [95%CI: 0.34-0.92] for RASi ( +) and RASi (-), respectively, p = 0.036) whereas no apparent difference in renal survival was noted for CCB. CONCLUSIONS: Early use of RASi contributes to the renal functional recovery from acute reduction in eGFR among patients with hypertensive emergencies. Furthermore, RASi offers more favorable effect on 2-year renal survival, compared with CCB.

Effectiveness of point of care ultrasound (POCUS) simulation course and skills retention for Japanese nurse practitioners.

BACKGROUND: In Japan, the nurse practitioner (NP) system has only been in place for a short time, and there is no ultrasound (US) simulation course for NPs. Therefore, NPs may have to attend US simulation courses for physicians. We evaluated whether US simulation course for physicians lead to improved image acquisition and interpretation amongst NPs and, if so, if these changes would be maintained over time. METHODS: A 2-day point-of-care ultrasound (POCUS) course designed for physicians in cardiac US, lung US, lower extremity deep vein thrombosis (DVT) US, and abdominal US was held for Japanese nurse practitioners (JNP) and JNP trainees in 2018 and 2019. Participants kept a record of the number of US examinations they performed for 3 months before and 3 months after the course. The number of US exams performed was grouped into six categories. All participants underwent pre-course, immediate post-course, and 4-month post-course testing to assess image interpretation skills, image acquisition skills, and confidence. RESULTS: Thirty-three participants from 21 facilities completed the program. Before and immediately after the course, test scores of the image interpretation test, image acquisition test, and confidence increased significantly (37.1, 72.6: P < 0.001), (13.7, 53.6: P < 0.001), and (15.8, 35.7: P < 0.001), respectively. Comparing the follow-up tests immediately after the course and 4 months later, there was no decrease in scores on the image interpretation test, the image acquisition test, or confidence (72.6, 71.8: P = 1.00) (53.6, 52.9: p = 1.00) (35.7, 33.0: P = 0.34). There was a statistically significant increase (P < 0.001) in both the total number of ultrasound examinations and in the number of ultrasound examinations by category (cardiac, lung, lower extremity DVT, and abdominal) in the 3 months before and 3 months after the course. CONCLUSIONS: The POCUS simulation course for physicians is useful for JNPs to acquire US examination skills even if it is not arranged for JNPs. Image interpretation skill, image acquisition skill, and confidence improved significantly and were maintained even after 4 months of the course. It leads to behavioral changes such as increasing the number of US examinations in daily practice after the course.

Estimation of the amount of pear pollen based on flowering stage detection using deep learning.

Pear pollination is performed by artificial pollination because the pollination rate through insect pollination is not stable. Pollen must be collected to secure sufficient pollen for artificial pollination. However, recently, collecting sufficient amounts of pollen in Japan has become difficult, resulting in increased imports from overseas. To solve this problem, improving the efficiency of pollen collection and strengthening the domestic supply and demand system is necessary. In this study, we proposed an Artificial Intelligence (AI)-based method to estimate the amount of pear pollen. The proposed method used a deep learning-based object detection algorithm, You Only Look Once (YOLO), to classify and detect flower shapes in five stages, from bud to flowering, and to estimate the pollen amount. In this study, the performance of the proposed method was discussed by analyzing the accuracy and error of classification for multiple flower varieties. Although this study only discussed the performance of estimating the amount of pollen collected, in the future, we aim to establish a technique for estimating the time of maximum pollen collection using the method proposed in this study.

Shape classification technology of pollinated tomato flowers for robotic implementation.

Three pollination methods are commonly used in the greenhouse cultivation of tomato. These are pollination using insects, artificial pollination (by manually vibrating flowers), and plant growth regulators. Insect pollination is the preferred natural technique. We propose a new pollination method, using flower classification technology with Artificial Intelligence (AI) administered by drones or robots. To pollinate tomato flowers, drones or robots must recognize and classify flowers that are ready to be pollinated. Therefore, we created an AI image classification system using a machine learning convolutional neural network (CNN). A challenge is to successfully classify flowers while the drone or robot is constantly moving. For example, when the plant is shaking due to wind or vibration caused by the drones or robots. The AI classifier was based on an image analysis algorithm for pollination flower shape. The experiment was performed in a tomato greenhouse and aimed for an accuracy rate of at least 70% for sufficient pollination. The most suitable flower shape was confirmed by the fruiting rate. Tomato fruit with the best shape were formed by this method. Although we targeted tomatoes, the AI image classification technology is adaptable for cultivating other species for a smart agricultural future.

Sustained effect of leukocytapheresis/granulocytapheresis versus anti-human TNF-α monoclonal antibody on ulcerative colitis: A 2-year retrospective study.

Although anti-tumor necrosis factor-α monoclonal antibody biological preparations (BP) agents are widely used as an established treatment tool for refractory ulcerative colitis (UC), whether leukocytapheresis/granulocytapheresis (L/G-CAP) has similar beneficial impact on the disease activity remains undetermined. Furthermore, the costs defrayed for the treatment with these 2 modalities have not been compared. We retrospectively evaluated whether L/G-CAP offered sustained beneficial effects over 2-year period. The patients who had moderately to severely active UC (Rachmilewitz clinical activity index (CAI) ≧ 5) and were treated with a series (10 sessions) of L/G-CAP (n = 19) or BP (n = 7) as an add-on therapy to conventional medications were followed. Furthermore, the cost-effectiveness pertaining to the treatment with L/G-CAP and BP was assessed over 12 months. At baseline, L/G-CAP and BP groups manifested similar disease activity (CAI, L/G-CAP; 7.0 [6.0-10.0], BP; 10.0 [6.0-10.0], P = .207). The L/G-CAP and BP treatment suppressed the activity, with CAI 1 or less attained on day 180. When the L/G-CAP group was dichotomized into L/G-CAP-high and L/G-CAP-low group based on CAI values (≥3 or < 3) on day 365, CAI was gradually elevated in L/G-CAP-high group but remained suppressed in L/G-CAP-low group without additional apheresis for 2 years. Anemia was corrected more rapidly and hemoglobin levels were higher in BP group. The cost of the treatment with L/G-CAP over 12 months was curtailed to 76% of that with BP (1.79 [1.73-1.92] vs 2.35 [2.29-3.19] million yen, P = .028). L/G-CAP is as effective as BP in a substantial number of patients over 2 years. The cost for the treatment of UC favors L/G-CAP although the correction of anemia may prefer BP. Thus, L/G-CAP can effectively manage the disease activity with no additional implementation for 2 years although further therapeutic modalities might be required in a certain population with high CAI observed on day 365.

Central organization of a high-dimensional odor space.

Animals recognize groups and mixtures of odors as a unitary object. This ability is crucial to generalize known odors to newly encountered ones despite variations. However, it remains largely unknown how multitudes of odors are represented and organized in the higher brain regions to support odor object recognition. Here we discuss recent advances uncovering the population odor responses in the rodent piriform cortex and the Drosophila mushroom body, and highlight the emerging principles on the organization, mechanism, stereotypy, and experience-dependence of central odor representations.

Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise caused by rapid resumption after prolonged detraining.

BACKGROUND: We report a case of acute renal failure with loin pain and patchy renal ischemia after anaerobic exercise (ALPE) caused by sudden training resumption. CASE PRESENTATION: A 19-year-old Asian man who was a college American football player presented with severe back pain, headache, and malaise. He developed acute kidney injury without myoglobinuria. Based on the typical medical history and symptoms, we made a diagnosis of ALPE. Symptoms improved within a few days, and serum creatinine levels simproved after discharge. He resumed training, adjusting his load step by step. CONCLUSION: During the coronavirus disease 2019 pandemic, many athletes were unable to undergo adequate training. Long-term de-training leads to decreased various organ function and reduces the anaerobic threshold. Rapid resumption after prolonged de-training may put individuals at risk of developing ALPE.

Notch signal organizes the Drosophila olfactory circuitry by diversifying the sensory neuronal lineages.

An essential feature of the organization and function of the vertebrate and insect olfactory systems is the generation of a variety of olfactory receptor neurons (ORNs) that have different specificities in regard to both odorant receptor expression and axonal targeting. Yet the underlying mechanisms that generate this neuronal diversity remain elusive. Here we demonstrate that the Notch signal is involved in the diversification of ORNs in Drosophila melanogaster. A systematic clonal analysis showed that a cluster of ORNs housed in each sensillum were differentiated into two classes, depending on the level of Notch activity in their sibling precursors. Notably, ORNs of different classes segregated their axonal projections into distinct domains in the antennal lobes. In addition, both the odorant receptor expression and the axonal targeting of ORNs were specified according to their Notch-mediated identities. Thus, Notch signaling contributes to the diversification of ORNs, thereby regulating multiple developmental events that establish the olfactory map in Drosophila.

Portal and Mesenteric Vein Thrombosis Associated with Hyperthyroidism.

BACKGROUND Non-malignant and non-cirrhotic portal and mesenteric vein thrombosis is rare. It has been reported that the hyperthyroid state is associated with increased risks of venous thrombosis due to increases in levels of various coagulation and anti-fibrinolytic factors. Particularly, changes in levels of these factors are also reported in cases of portal and mesenteric vein thrombosis. Although hyperthyroidism is not known as a risk factor for portal and mesenteric vein thrombosis, it might be an underlying pathogenesis of hyperthyroidism-associated portal and mesenteric vein thrombosis. CASE REPORT A 59-year-old Japanese man with a history of Grave's disease presented with acute portal and mesenteric vein thrombosis and hyperthyroidism. Anticoagulation therapy was initiated and the dose of antithyroid drug was increased. He underwent various tests to identify causes of portal and mesenteric vein thrombosis. However, all test results were within normal range except for hyperthyroidism. Therefore, we discontinued anticoagulation therapy after normalization of thyroid hormone status. After 3 years, he experienced recurrence of portal vein thrombosis concomitant with hyperthyroidism. CONCLUSIONS Hyperthyroidism might be associated with portal vein thrombosis. Thyroid function tests should be performed in cases of portal and mesenteric vein thrombosis in the absence of other risk factors.

Effects of SGLT2 inhibitors on eGFR in type 2 diabetic patients-the role of antidiabetic and antihypertensive medications.

Recent randomized trials demonstrating the beneficial effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in type 2 diabetes suggest that early reductions in eGFR upon initiation of SGLT2i therapy are associated with improved renal outcomes. Multiple concomitant medications, including antidiabetic and antihypertensive agents, are commonly used, however, which may modify the renal hemodynamic action of SGLT2is. Here we found that background treatment with metformin diminished the SGLT2i-induced reductions in eGFR after 3 months of SGLT2i therapy in patients with type 2 diabetes and hypertension (-2.29 ± 0.90 vs -5.85 ± 1.27 mL/min/1.73 m2 for metformin users (n = 126) and nonusers (n = 97), respectively). Other antidiabetic agents (DPP4 inhibitors, sulfonylureas and insulin) had no effect on the eGFR response to SGLT2is. Antihypertensive drugs, including calcium channel blockers (CCBs) and ß blockers, did not affect the SGLT2i-induced changes in eGFR, whereas renin-angiotensin system inhibitors (RASis) tended to enhance this response (p = 0.059). Next, we evaluated the interaction between metformin and RASis in the eGFR responses to SGLT2is. Under no background treatment with RASis, metformin abrogated the eGFR response to SGLT2is, but this response was preserved when RASis had been given along with metformin (decreases of 0.75 ± 1.28 vs. 4.60 ± 1.15 mL/min/1.73 m2 in eGFR, p = 0.028). No interaction between metformin and insulin or between metformin and DPP4 inhibitors was observed. In conclusion, metformin blunts the SGLT2i-induced decrease in eGFR, but coadministration of RASis ameliorates this response. Furthermore, the inability of CCBs to modify the SGLT2i-induced reduction in eGFR suggests that the SGLT2i-induced renal microvascular action is mediated predominantly by postglomerular vasodilation rather than preglomerular vasoconstriction.

Differentially expressed Drl and Drl-2 play opposing roles in Wnt5 signaling during Drosophila olfactory system development.

In Drosophila, odor information received by olfactory receptor neurons (ORNs) is processed by glomeruli, which are organized in a stereotypic manner in the antennal lobe (AL). This glomerular organization is regulated by Wnt5 signaling. In the embryonic CNS, Wnt5 signaling is transduced by the Drl receptor, a member of the Ryk family. During development of the olfactory system, however, it is antagonized by Drl. Here, we identify Drl-2 as a receptor mediating Wnt5 signaling. Drl is found in the neurites of brain cells in the AL and specific glia, whereas Drl-2 is predominantly found in subsets of growing ORN axons. A drl-2 mutation produces only mild deficits in glomerular patterning, but when it is combined with a drl mutation, the phenotype is exacerbated and more closely resembles the Wnt5 phenotype. Wnt5 overexpression in ORNs induces aberrant glomeruli positioning. This phenotype is ameliorated in the drl-2 mutant background, indicating that Drl-2 mediates Wnt5 signaling. In contrast, forced expression of Drl-2 in the glia of drl mutants rescues the glomerular phenotype caused by the loss of antagonistic Drl function. Therefore, Drl-2 can also antagonize Wnt5 signaling. Additionally, our genetic data suggest that Drl localized to developing glomeruli mediates Wnt5 signaling. Thus, these two members of the Ryk family are capable of carrying out a similar molecular function, but they can play opposing roles in Wnt5 signaling, depending on the type of cells in which they are expressed. These molecules work cooperatively to establish the olfactory circuitry in Drosophila.

Synthesis of Conserved Odor Object Representations in a Random, Divergent-Convergent Network.

Animals are capable of recognizing mixtures and groups of odors as a unitary object. However, how odor object representations are generated in the brain remains elusive. Here, we investigate sensory transformation between the primary olfactory center and its downstream region, the mushroom body (MB), in Drosophila and show that clustered representations for mixtures and groups of odors emerge in the MB at the population and single-cell levels. Decoding analyses demonstrate that neurons selective for mixtures and groups enhance odor generalization. Responses of these neurons and those selective for individual odors all emerge in an experimentally well-constrained model implementing divergent-convergent, random connectivity between the primary center and the MB. Furthermore, we found that relative odor representations are conserved across animals despite this random connectivity. Our results show that the generation of distinct representations for individual odors and groups and mixtures of odors in the MB can be understood in a unified computational and mechanistic framework.

Difference in BPA uptake between glioma stem-like cells and their cancerous cells.

Tumor sphere-forming (TS) glioma stem cells and cancerous TS cells were analyzed in vivo and in vitro. The boron concentration in murine TS tumors was higher than normal tissue. The boron concentration at 24 h was 0.80 ± 0.09 µg/107 in the TS cells, and 1.08 ± 0.08 µg/107 in the cancerous cells. The LAT-1 amino-acid transporter positive rate was 35.4% in the TS cells and 100% in the cancerous cells. These results suggested the relation between LAT-1 expression and boronophenylalanine concentration in vitro.

Boron analysis and imaging of cells with 2-hr BPA exposure by using micro-proton particle-induced gamma-ray emission (PIGE).

Particle-induced gamma-ray emission (PIGE), which measures prompt gamma rays at 428 keV from 10B (p, p'γ) 7Be, was used to confirm the boron distribution within 2hr-BPA-exposed cells. Distribution images of potassium, phosphate, and boron and the whole spectrum showed the ratios of boron counts to total (%) as follows: control group: 1.35 ± 0.073%; 2hr boron exposure group: 2.33 ± 0.35%; and boron exposure/wash group: 1.58 ± 0.095%. Micro-beam PIXE/PIGE can be a promising tool for visualization of intracellular Boron.

Early development of the Drosophila mushroom bodies, brain centres for associative learning and memory.

We have studied the formation of Drosophila mushroom bodies using enhancer detector techniques to visualize specific components of these complex intrinsic brain structures. During embryogenesis, neuronal proliferation begins in four mushroom body neuroblasts and the major axonal pathways of the mushroom bodies are pioneered. During larval development, neuronal proliferation continues and further axonal projections in the pedunculus and lobes are formed in a highly structured manner characterized by spatial heterogeneity of reporter gene expression. Enhancer detector analysis identifies many genomic locations that are specifically activated in mushroom body intrinsic neurons (Kenyon cells) during the transition from embryonic to postembryonic development and during metamorphosis.

Nonradioactive In Situ Hybridization Methods for Drosophila Embryos Detecting Signals by Immunogold-Silver or Immunoperoxidase Method for Electron Microscopy: (electron microscopy/pre-embedding/transcripts/Drosophila embryo).

We present details of in situ hybridization methods for electron microscopy applicable for Drosophila embryos. Improvements upon the foregoing methods were made at 1) hybridization and visualization of signals were carried out with whole embryos that were then processed for electron microscopy, and 2) digoxigenin-labeled probes were detected by the immunogold silver enhancement method or by the immunoperoxidase method. Using these methods. we demonstrated the localization of fushi tarazu transcripts in the apical region of blastodermal cells. We also showed that mitochondrial large ribosomal RNA is associated with polar granules in pole plasm of cleavage embryos. These methods will make a useful tool to determine the precise subcellular distribution of specific transcripts in Drosophila embryos.

Whole mount immunolabeling of olfactory receptor neurons in the Drosophila antenna.

Odorant molecules bind to their target receptors in a precise and coordinated manner. Each receptor recognizes a specific signal and relays this information to the brain. As such, determining how olfactory information is transferred to the brain, modifying both perception and behavior, merits investigation. Interestingly, there is emerging evidence that cellular transduction and transcriptional factors are involved in the diversification of olfactory receptor neuron. Here we provide a robust whole mount immunological labeling method to assay in vivo olfactory receptor neuron organization. Using this method, we identified all olfactory receptor neurons with anti-ELAV antibody, a known pan-neural marker and Or49a-mCD8::GFP, an olfactory receptor neuron specifically expressed in Nba neuron using anti-GFP antibody.

Systematic analysis of neural projections reveals clonal composition of the Drosophila brain.

BACKGROUND: During development neurons are generated by sequential divisions of neural stem cells, or neuroblasts. In the insect brain progeny of certain stem cells form lineage-specific sets of projections that arborize in distinct brain regions, called clonal units. Though this raises the possibility that the entire neural network in the brain might be organized in a clone-dependent fashion, only a small portion of clones has been identified. RESULTS: Using Drosophila melanogaster, we randomly labeled one of about 100 stem cells at the beginning of the larval stage, analyzed the projection patterns of their progeny in the adult, and identified 96 clonal units in the central part of the fly brain, the cerebrum. Neurons of all the clones arborize in distinct regions of the brain, though many clones feature heterogeneous groups of neurons in terms of their projection patterns and neurotransmitters. Arborizations of clones overlap preferentially to form several groups of closely associated clones. Fascicles and commissures were all made by unique sets of clones. Whereas well-investigated brain regions such as the mushroom body and central complex consist of relatively small numbers of clones and are specifically connected with a limited number of neuropils, seemingly disorganized neuropils surrounding them are composed by a much larger number of clones and have extensive specific connections with many other neuropils. CONCLUSIONS: Our study showed that the insect brain is formed by a composition of cell-lineage-dependent modules. Clonal analysis reveals organized architecture even in those neuropils without obvious structural landmarks.

Organization of antennal lobe-associated neurons in adult Drosophila melanogaster brain.

The primary olfactory centers of both vertebrates and insects are characterized by glomerular structure. Each glomerulus receives sensory input from a specific type of olfactory sensory neurons, creating a topographic map of the odor quality. The primary olfactory center is also innervated by various types of neurons such as local neurons, output projection neurons (PNs), and centrifugal neurons from higher brain regions. Although recent studies have revealed how olfactory sensory input is conveyed to each glomerulus, it still remains unclear how the information is integrated and conveyed to other brain areas. By using the GAL4 enhancer-trap system, we conducted a systematic mapping of the neurons associated with the primary olfactory center of Drosophila, the antennal lobe (AL). We identified in total 29 types of neurons, among which 13 are newly identified in the present study. Analyses of arborizations of these neurons in the AL revealed how glomeruli are linked with each other, how different PNs link these glomeruli with multiple secondary sites, and how these secondary sites are organized by the projections of the AL-associated neurons.