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Non-small cell lung cancer (NSCLC) patients are often complicated by other respiratory diseases, including interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB), and the management of which can be problematic. NSCLC patients with IP sometimes develop fatal acute exacerbation induced by pharmacotherapy, and the establishment of a safe treatment strategy is desirable. For advanced NSCLC with IP, carboplatin plus nanoparticle albumin-bound paclitaxel is a relatively safe and effective first-line treatment option. Although the safety of immune checkpoint inhibitors (ICIs) for these populations remains controversial, ICIs have the potential to provide long-term survival. The severity of COPD is an important prognostic factor in NSCLC patients. Although COPD complications do not necessarily limit treatment options, it is important to select drugs with fewer side effects on the heart and blood vessels as well as the lungs. Active TB is complicated by 2-5% of NSCLC cases during their disease course. Since pharmacotherapy, especially ICIs, reportedly induces the development of TB, the possibility of developing TB should always be kept in mind during NSCLC treatment. To date, there is no coherent review article on NSCLC with these pulmonary complications. This review article summarizes the current evidence and discusses future prospects for treatment strategies for NSCLC patients complicated with IP, severe COPD, and TB.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRAS G12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRAS G12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRAS G12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRAS G12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

In domain adaptation, when there is a large distance between the source and target domains, the prediction performance will degrade. Gradual domain adaptation is one of the solutions to such an issue, assuming that we have access to intermediate domains, which shift gradually from the source to the target domain. In previous works, it was assumed that the number of samples in the intermediate domains was sufficiently large; hence, self-training was possible without the need for labeled data. If the number of accessible intermediate domains is restricted, the distances between domains become large, and self-training will fail. Practically, the cost of samples in intermediate domains will vary, and it is natural to consider that the closer an intermediate domain is to the target domain, the higher the cost of obtaining samples from the intermediate domain is. To solve the trade-off between cost and accuracy, we propose a framework that combines multifidelity and active domain adaptation. The effectiveness of the proposed method is evaluated by experiments with real-world datasets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Juvenile Idiopathic Arthritis (JIA) is associated with joint inflammation, pain and limited joint mobility, impacting the practice of physical activities. Adapted Physical Activities (APA) are an increasingly used method of rehabilitation, but additional studies are needed to define the nature of the most appropriate physical activity for patients with JIA. The "ATHLETIQUE" project aims to evaluate the impact of a program integrating APA sessions with use of a pedometer watch, on disease activity in patients with JIA., Methods: This study will be a randomized, multicenter, open-label, controlled clinical trial with 2 parallel arms. The patients included in this study will be children and adolescents with JIA, aged 6 to 17 years. The experimental group (30 patients) will participate in an APA program for 3 months and will use a pedometer watch for one year. We will evaluate and compare the change in disease activity measurements (primary objective), fatigue, pain, quality of life, level of physical activity, functional capacities, and muscle strength (secondary objectives) after 14, 26 and 50 weeks. The control group (10 patients) will undergo the same evaluations as the experimental group but will not participate in the APA program and will not wear the pedometer watch., Expected Results: The APA program may help to promote an active lifestyle with regular physical activity, preventing comorbidities and motor disability. Promising results on disease activity, functional capacities and quality of life would enable us to envisage a larger research program with a view to optimizing and assessing APA for children with JIA., Discussion: This study will be conducted in the short and medium-term, with one-year follow-up, including 3 months of APA sessions for the experimental group. The sessions proposed during the APA program will mainly be aerobic and bodyweight exercises. Furthermore, in contrast to previous studies on this topic, our study will integrate a novel element, namely the use of a pedometer watch. This watch will help to implement strategies to address motivation. This study aims to improve physical and mental well-being, provide a basis for the design of a larger study, and propose recommendations adapted to children with JIA., Trial Registration: Registered with ClinicalTrials.gov under the number NCT05572424., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Py, Maylié, Parmentier, Vidal, Cuinet, Mauny, Lohse, Toussirot, Yoshimasa, Tordi, Binda and Ballot-Schmit.)

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Watase et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)-which performs its function by forming a PPI with its receptor-without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein-small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2-small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YS, VPM, AEL, ETK, and SS are former paid employees of D. E. Shaw Research; DES is the sole beneficial owner and Chief Scientist of D. E. Shaw Research.

Objective: To investigate the association between the Simple Swallowing Provocation Test (SSPT) and the incidence of aspiration pneumonia in patients with dysphagia in long-term care (LTC) wards., Design: The study design was a prospective cohort study. Participants were followed for 60 days from admission., Setting: LTC wards., Participants: Study participants were patients with dysphagia aged ≥65 years who were admitted to LTC wards between August 2018 and August 2019. In total, 39 participants were included in the analysis (N=39; 20 male, 19 female; mean age, 83.8±8.5y). Participants were divided into 2 groups based on SSPT results: normal swallowing reflex (SSPT normal group) and abnormal swallowing reflex (SSPT abnormal group). The covariates were age and sex, primary disease, history of cerebrovascular disease, Glasgow Coma Scale, body mass index, Geriatric Nutritional Risk Index, the Mann Assessment of Swallowing Ability, Food Intake Level Scale, FIM, and Oral Health Assessment Tool., Interventions: Not applicable., Main Outcome Measures: The outcome was the incidence of aspiration pneumonia during the first 60 days of hospitalization, and the predictive factor was SSPT: 0.4 mL., Results: The incidence of aspiration pneumonia was 33.3% in the SSPT normal group and 76.2% in the SSPT abnormal group. The φ coefficient (a measure of association for 2 binary variables) was 0.43, the risk ratio (the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group) was 2.29, and the 95% confidence interval was 1.14-4.58 for the SSPT abnormal group., Conclusions: Our findings suggest that the SSPT provides a valid index for the development of aspiration pneumonia in older patients with dysphagia admitted to LTC wards., (Copyright © 2021 The American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Interkingdom competition occurs between hymenopteran parasitoids and insect viruses sharing the same insect hosts. It has been assumed that parasitoid larvae die with the death of the infected host or as result of competition for host resources. Here we describe a gene family, parasitoid killing factor ( pkf ), that encodes proteins toxic to parasitoids of the Microgastrinae group and determines parasitism success. Pkfs are found in several entomopathogenic DNA virus families and in some lepidopteran genomes. We provide evidence of equivalent and specific toxicity against endoparasites for PKFs found in entomopoxvirus, ascovirus, baculovirus, and Lepidoptera through a mechanism that elicits apoptosis in the cells of susceptible parasitoids. This highlights the evolutionary arms race between parasitoids, viruses, and their insect hosts., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Bruton's tyrosine kinase (Btk) is critical for B cell proliferation and activation, and the development of Btk inhibitors is a vigorously pursued strategy for the treatment of various B cell malignancies. A detailed mechanistic understanding of Btk activation has, however, been lacking. Here, inspired by a previous suggestion that Btk activation might depend on dimerization of its lipid-binding PH-TH module on the cell membrane, we performed long-timescale molecular dynamics simulations of membrane-bound PH-TH modules and observed that they dimerized into a single predominant conformation. We found that the phospholipid PIP 3 stabilized the dimer allosterically by binding at multiple sites, and that the effects of PH-TH mutations on dimer stability were consistent with their known effects on Btk activity. Taken together, our simulation results strongly suggest that PIP 3 -mediated dimerization of Btk at the cell membrane is a critical step in Btk activation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain.

The family Ascoviridae is a recently described virus family whose members are transmitted by parasitoids and cause chronic and lethal infections in lepidopteran insects. Little is known about the biology and ecology of ascoviruses, and few isolates have been found outside the United States. We report here the isolation of a new ascovirus variant from Spodoptera litura in Japan. Full genome sequence and phylogenetic analyses showed that this virus was closely related to variants in Heliothis virescens ascovirus-3a, and it was named HvAV-3j. HvAV-3j has a DNA genome of 191 718 bp, with 189 putative ORFs and a GC content of 45.6 %, and is highly similar to HvAV-3h, which was isolated in China. In a field survey, the endoparasitoid Meteorus pulchricornis caused a high percentage of parasitization in populations of S. litura larvae, and under laboratory conditions M. pulchricornis was able to transmit HvAV-3j from infected to uninfected larvae by oviposition. Meteorus pulchricornis is thus likely to be a major vector for HvAV-3j transmission in Japan. This species is recognized here for the first time as a vector of ascoviruses that parasitizes a range of host species that extends across families.

Although transcriptional regulation is fundamental to understanding bacterial physiology, the targets of most bacterial transcription factors are not known. Comparative genomics has been used to identify likely targets of some of these transcription factors, but these predictions typically lack experimental support. Here, we used mutant fitness data, which measures the importance of each gene for a bacterium's growth across many conditions, to test regulatory predictions from RegPrecise, a curated collection of comparative genomics predictions. Because characterized transcription factors often have correlated fitness with one of their targets (either positively or negatively), correlated fitness patterns provide support for the comparative genomics predictions. At a false discovery rate of 3%, we identified significant cofitness for at least one target of 158 TFs in 107 ortholog groups and from 24 bacteria. Thus, high-throughput genetics can be used to identify a high-confidence subset of the sequence-based regulatory predictions.

We report herein a new molecular catalyst for efficient water splitting, aluminum porphyrins (tetra-methylpyridiniumylporphyrinatealuminum: AlTMPyP), containing earth's most abundant metal as the central ion. One-electron oxidation of the aluminum porphyrin initiates the two-electron oxidation of water to form hydrogen peroxide as the primary reaction product with the lowest known overpotential (97 mV). The aluminum-peroxo complex was detected by a cold-spray ionization mass-spectrometry in high-resolution MS (HRMS) mode and the structure of the intermediate species was further confirmed using laser Raman spectroscopy, indicating the hydroperoxy complex of AlTMPyP to be the key intermediate in the reaction. The two-electron oxidation of water to form hydrogen peroxide was essentially quantitative, with a Faradaic efficiency of 99 %. The catalytic reaction was found to be highly efficient, with a turnover frequency up to ∼2×10 4  s -1 . A reaction mechanism is proposed involving oxygen-oxygen bond formation by the attack of a hydroxide ion on the oxyl-radical-like axial ligand oxygen atom in the one-electron-oxidized form of AlTMPyP(O - ) 2 , followed by a second electron transfer to the electrode., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We describe here the Genotype Specification Language (GSL), a language that facilitates the rapid design of large and complex DNA constructs used to engineer genomes. The GSL compiler implements a high-level language based on traditional genetic notation, as well as a set of low-level DNA manipulation primitives. The language allows facile incorporation of parts from a library of cloned DNA constructs and from the "natural" library of parts in fully sequenced and annotated genomes. GSL was designed to engage genetic engineers in their native language while providing a framework for higher level abstract tooling. To this end we define four language levels, Level 0 (literal DNA sequence) through Level 3, with increasing abstraction of part selection and construction paths. GSL targets an intermediate language based on DNA slices that translates efficiently into a wide range of final output formats, such as FASTA and GenBank, and includes formats that specify instructions and materials such as oligonucleotide primers to allow the physical construction of the GSL designs by individual strain engineers or an automated DNA assembly core facility.

Small RNAs (sRNAs) are important regulators of gene expression during bacterial stress and pathogenesis. sRNAs act by forming duplexes with mRNAs to alter their translation and degradation. In some bacteria, duplex formation is mediated by the Hfq protein, which can bind the sRNA and mRNA in each pair in a random order. Here we investigate the consequences of this random-order binding and experimentally demonstrate that it can counterintuitively cause high Hfq concentrations to suppress rather than promote sRNA activity in Escherichia coli. As a result, maximum sRNA activity occurs when the Hfq concentration is neither too low nor too high relative to the sRNA and mRNA concentrations ('Hfq set-point'). We further show with models and experiments that random-order binding combined with the formation of a dead-end mRNA-Hfq complex causes high concentrations of an mRNA to inhibit its own duplex formation by sequestering Hfq. In such cases, maximum sRNA activity requires an optimal mRNA concentration ('mRNA set-point') as well as an optimal Hfq concentration. The Hfq and mRNA set-points generate novel regulatory properties that can be harnessed by native and synthetic gene circuits to provide greater control over sRNA activity, generate non-monotonic responses and enhance the robustness of expression., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Mechanisms that control cell-to-cell variation in gene expression ('phenotypic variation') can determine a population's growth rate, robustness, adaptability and capacity for complex behaviours. Here we describe a general strategy (termed FABMOS) for tuning the phenotypic variation and mean expression of cell populations by modulating the frequency and bias of stochastic transitions between 'OFF' and 'ON' expression states of a genetic switch. We validated the strategy experimentally using a synthetic fim switch in Escherichia coli. Modulating the frequency of switching can generate a bimodal (low frequency) or a unimodal (high frequency) population distribution with the same mean expression. Modulating the bias as well as the frequency of switching can generate a spectrum of bimodal and unimodal distributions with the same mean expression. This remarkable control over phenotypic variation, which cannot be easily achieved with standard gene regulatory mechanisms, has many potential applications for synthetic biology, engineered microbial ecosystems and experimental evolution.

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido[4,5-b][1,4]oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid 1, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of 1 was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane 42, which displayed significantly improved DGAT1 inhibition compared to 1. Spiroindane 42 was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies.

We isolated cDNA for a luciferase isotype, LlLuc2, from the ovary of the Japanese firefly, Luciola lateralis. The gene product LlLuc2 showed 59% amino acid identity with LlLuc1, which had been isolated from the adult L. lateralis lantern. Molecular phylogenetic analysis indicated that LlLuc2 is an orthologue of LcLuc2 from Luciola cruciata. The spectral maxima of the luminescence by recombinant LlLuc1 and LlLuc2 were 550 and 539 nm, respectively. Quantitative PCR analysis revealed that LlLuc1 was expressed predominantly in larvae and adults, and LlLuc2 was expressed in eggs and pupae, which glow dimly, and we found that the in vivo luminescence spectra of the egg and pupa in L. lateralis were in good agreement with the in vitro luminescence spectrum by LlLuc2. These results suggest that, in L. lateralis, LlLuc1 is responsible for the yellowish luminescence of larval and adult lanterns, and LlLuc2 is responsible for the dim, greenish glow of eggs and whole pupae. Similar results were obtained in L. cruciata.

Japan is an earthquake-prone country, and disasters have a devastating effect on the lives of residents in stricken areas. Shelters can be constructed in order to secure the physical safety of residents, but there are no such provisions for the shock of experiencing a disaster, losing property and friends, and transitioning to an unfamiliar life in a shelter, all of which can lead to mental disorders. Caretakers such as medical doctors and nurses who are dispatched to disaster sites also face difficulties in the disruption of communications and transportation, thus a system able to secure efficient health management in those facilities is also required. This paper proposes a health information management system that utilizes mobile phone cameras and mark-sensing cards to improve recovery conditions in disaster-stricken areas.

Mitochondria are organelles that produce ATP and reactive oxygen species, which are thought to be responsible for a decline in physiological function with aging. In this study, we morphologically and biochemically examined mitochondria in the rat adrenal gland. Immunohistochemistry showed that the rank order for intensity of immunolabelling for complex IV was zona reticularis > zona fasciculata >> adrenal medulla, whereas for complex V α and β subunits, it was zona fasciculata > zona reticularis and adrenal medulla. The immunolabelling for complex I was homogeneous in the adrenal gland. The difference in immunolabelling between complexes I and IV indicates that the ratio of levels of complex I to that of complex IV in the zona reticularis was smaller than that in the zona fasciculata and the adrenal medulla. Electron microscopy revealed that aging rats had zona reticularis cells with many lysosomes and irregular nuclei. The result suggests that the level of proteins involved in oxidative phosphorylation is coordinated within the complex, but differs between the complexes. This might be responsible for degeneration of zona reticularis cells with aging., (Copyright © 2009 Elsevier GmbH. All rights reserved.)

A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 μM to 48 nM., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Lower body negative pressure (LBNP) induces venous pooling in the legs and a decrease of blood volume (BV). The present study was designed to investigate the dynamic changes in BV and limb volume during LBNP. We made continuous measurements of blood density (h) during LBNP at two different levels (-15 and -30 mmHg) in eight healthy male volunteers. Blood was withdrawn continuously from the antecubital vein to measure rho b during an experimental period of 40 min (a 10-min control period, a 10-min LBNP and a 20-min recovery period). The density was measured by the mechanical oscillator technique. The changes of circumference in the upper arm and calf were measured by strain gauge plethysmography. Rho b decreased rapidly in the early phase of LBNP followed by an increase, as expected. The peak reduction (-0.35 +/- 0.04 g/l) of rho b at -15 mmHg did not differ (P = 0.47) from that (-0.42 +/- 0.05 g/l) at -30 mmHg. The time (2.9 +/- 0.3 min) from onset of LBNP to the peak reduction of rho b was not significantly different between -15 and -30 mmHg (P = 0.50). After LBNP, a further rho b increase was continued for 2.5 +/- 0.2 min at both intensities, followed by the return toward control levels. The maximal increase (1.34 +/- 0.07 g/l) of rho b after LBNP at -30 mmHg was greater (P < 0.001) than that (0.57 +/- 0.06 g/l) at -15 mmHg. LBNP decreased the arm circumference and increased the calf circumference in an intensity-dependent manner. These results suggest that LBNP induces an intensity-dependent decrease in BV with no difference in the time peak reduction occurring after LBNP. We found no significant difference between the intensities in the transient hemodilution effect during LBNP. It is suggested that LBNP also induces an intensity-dependent mobilization of blood from the upper portion to the lower portion of the body.

We compared the dietary effects of dihomo-gamma-linolenic acid (DGLA) contained in the DGLA oil produced by a fungus with gamma-linolenic acid (GLA) on the fatty acid composition. Wistar rats were fed with three kinds of oil for two weeks as follows: (i) control group: corn oil; (ii) GLA group: borage oil; (iii) DGLA group: DGLA oil/safflower oil = 55:45. The DGLA concentrations in the liver, serum, and brain of the DGLA group were higher than those of the GLA oil group. We also examined the dose effect of DGLA. The DGLA levels in the liver, serum, and brain significantly increased with increasing dosage of DGLA in the diet. DGLA administration significantly increased the ratio of PGE1/PGE2 in the rat plasma. The mechanism for GLA administration to improve atopic eczema is thought to involve an increase in the concentration of DGLA metabolized from GLA, so these results suggest that the dietary effect of DGLA would be more dominant than GLA.

Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.

Aim: Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined., Methods: PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests., Results: JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher., Conclusions: These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.

Introduction: Accumulated evidence indicates attenuated vasopressin (AVP) release associated with hyperbaria in humans. The present study was designed to test the hypothesis that plasma AVP response to central hypovolemia was attenuated in a hyperbaric environment., Methods: Response of AVP to central hypovolemic stress, in the form of lower-body negative pressure (LBNP), was measured in 10 men at 1 and 3 atmosphere absolute (ATA) air. The stress consisted of 4 min each of control and LBNP at -20 and -40 mmHg. Plasma AVP, plasma norepinephrine (NE), plasma osmolality, and hematocrit (Hct) were measured. Thoracic impedance (Z0), and leg volume were also determined., Results: The baseline AVP (0.9 +/- 0.3 pg x ml(-1)) at 1 ATA increased significantly in response to -40 mmHg LBNP (1.8 +/- 0.6 pg x ml(-1)), but the increase was attenuated at 3 ATA (1.2 +/- 0.8 pg x ml(-1)). The baseline NE at 3 ATA was lower by 22.4 pg x ml(-1) than that of 1 ATA (226.5 pg x ml(-1)). NE increased with increasing LBNP at both environmental pressures, but the increase was independent of the pressure. Changes in Z0, reflecting thoracic blood volume, were identical in both environments. Mean arterial pressure, plasma osmolality, and Hct remained constant throughout the experimental period. Leg volume increased stress dependently during LBNP (approximately 34 ml at -20 mmHg; approximately 74 ml at -40 mmHg) and the increment was similar in the two environments., Conclusion: The present study revealed that hyperbaria attenuated the response of AVP and NE to hypovolemic stress. The attenuated AVP response to LBNP was associated with neither plasma osmolality nor intrathoracic blood shift.

We report herein synthesis of PKCbeta-selective inhibitors possessing the novel pharmacophore of anilino-monoindolylmaleimide. Several compounds of this series exhibited IC50's as low as 50 nM against human PKCbeta2. One of the most potent compounds, 6l, inhibited PKCbeta1 and PKCbeta2 with IC50 of 21 and 5 nM, respectively, and exhibited selectivity of more than 60-fold in favor of PKCbeta2 relative to other PKC isozymes (PKCalpha, PKCgamma, and PKCepsilon).

Near-infrared spectroscopy (NIRS) was used to measure frontal regional cerebral blood volume (rCBV) in a person whose brain was under the influence of pharmacological agents while the person was performing a complex task. Fourteen healthy participants were administered Uchida-Kraepelin psychodiagnostic (UKP) tests before and after caffeine intake, and the concentration of caffeine in the urine was measured. The average number of answers and the average number of correct answers given by the participants improved significantly following caffeine intake. During the UKP testing, changes in the rCBV in the inferior frontal cortex were continuously measured using NIRS. The volume during the rest periods decreased as a result of caffeine-induced constriction of the cerebral arteriola. The volume increased during the mental work, but the degree of the increase was the same before and after caffeine intake. Although the performance of the mental work improved following caffeine intake, the improvement was not reflected in the rCBV in the inferior frontal cerebral cortex. These results suggest that caffeine helps to protect the brain from excessive hyperemia in addition to activating the neurons in the prefrontal cortex.

To test the hypothesis that tolerance to central hypovolemic stress is diminished with a reduced sensitivity of cardiac baroreflex in young and old men, twenty-four healthy elderly male subjects (67.5+/-0.9 yrs) and 24 young male subjects (22.4+/-0.4 yrs) underwent a 21 min bout of ramped lower body negative pressure (LBNP) (0 to -60 mmHg, 10 mmHg each for 3 min). Heart rate(HR), blood pressure, thoracic impedance (Z0) and calf circumference were measured throughout the experimental period. The sensitivity (BRS) of arterial baroreflex control of the cardiac interval was calculated from spontaneous changes in beat-to-beat arterial pressure and the RR interval during the LBNP test. The occurrence of presyncope episodes during LBNP was 16.7% in elderly subjects and 37.5% in young subjects. The changes of HR, blood pressure, Z0 and calf circumference in the young (Young fainter group) and the elderly (Elderly fainter group) subjects who showed presyncope during LBNP did not differ from those in the subjects (Young and Elderly nonfainter groups) who did not show presyncope. The steady-state HR responses to the changes of Z0 during LBNP did not differ among the four groups. In young and elderly subjects, the baseline values of BRS in the fainter groups tended to be smaller than those in the nonfainter groups, and the difference in the young group was significant (P<0.05). No LBNP-related change of BRS was observed in elderly subjects, whereas a gradual LBNP-related decrease was observed in young subjects. These findings suggest that 1) aging does not increase intolerance to central hypovolemic stress induced by a given LBNP, 2) the reduced vagal BRS is related partly to low LBNP tolerance in young and elderly men.

Background: This experiment was designed to examine the involvement of the autonomic nervous systems and intrinsic component in the occurrence of hyperbaric bradycardia., Methods: Eight male divers were exposed to a N2-O2 (Nitrox) environment at 3 atmospheres absolute (ATA) for 7 d. The heart rate (HR), plasma norepinephrine (NE), and a spectral power of the variability of cardiac interval were measured during a 4-d predive control period, a 7-d saturation period at 3 ATA, and a 4-d postdive period. In each dive period, atropine and propranolol were administered intravenously for cholinergic blockade and beta-adrenergic blockade, respectively., Results: Basal HR decreased by -10% (p < 0.05) during the saturation period compared with that of the predive control. The HR after an administration of atropine was attenuated by 5.5 +/- 2.4% (p < 0.05) during hyperbaric exposure. The HR after a simultaneous administration of atropine and propranolol, the intrinsic HR, was similar throughout the dive periods. Plasma NE decreased at 3 ATA (p < 0.05). The basal level of high-frequency power of cardiac interval variability, an index of cardiac parasympathetic modulation, remained unchanged throughout the dive period, whereas this power was eliminated by atropine administration., Conclusions: These results suggest that reduced sympathetic activity plays a primary role in the reduction of HR in the present hyperbaric environment.

The present experiment was carried out to examine the possible effects of whole body heating on the baroreflex control of muscle sympathetic nerve activity (MSNA) and heart rate (HR). Nine healthy male volunteers underwent the Valsalva maneuver during exposure to heat stress using a hot water-perfused suit. To exclude an effect from the unloading of the cardiopulmonary baroreceptors during hyperthermia, the central hypovolemia was counterbalanced by head-down tilt (HDT) at 8 degrees. The baroreflex slopes of MSNA and HR against mean arterial pressure were determined by regression analysis during the early phase II (falling blood pressure period) of the Valsalva maneuver. The core temperature increased from 36.9 +/- 0.1 degrees C at thermoneutral to 37.7 +/- 0.1 degrees C during heat exposure, whereas the left atrial diameter (LAD) decreased. Both the MSNA and HR increased (P < 0.05) during hyperthermia. The baroreflex slopes of MSNA and HR in the phase II decreased 30 +/- 8% (P < 0.05) and 24 +/- 9% (P < 0.05), respectively, during hyperthermia. The HDT increased LAD, but there was no change in HR, arterial pressure and the baroreflex slopes. These results suggest that hyperthermia reduces the baroreflex responses of MSNA and HR during a transient falling period of blood pressure. These reduced baroreflex responses may not be attributable to an unloading of the cardiopulmonary baroreceptors during heat stress., (Copyright 2002 Elsevier Science B.V.)

To investigate the possible involvement of the sympathetic nervous system in pressor response during water drinking, muscle sympathetic nerve activity (MSNA), blood pressure (BP), and heart rate (HR) were continuously measured in healthy young volunteers throughout the experiments of a 5-min control, 2 min of drinking 500 ml water, and a 28-min recovery. To avoid the effects of water passing through the oropharyngeal and esophageal regions and/or effects of swallowing, an equal amount of water was directly infused to the stomach through a stomach tube for 2 min. Water drinking caused a transient increase in mean arterial pressure (MAP) and HR immediately after drinking (DeltaMAP, 12.6 +/- 2.1 mmHg; DeltaHR, +19.9 +/- 1.7 beats/min at the peak). An abrupt decrease of MSNA was observed directly during water drinking (Deltaburst rate, -6.9 +/- 1.3 bursts/min; Deltatotal activity, -2,606 +/- 491 U/min), and it increased to the baseline level thereafter. Gastric infusion had little or no effect on MAP, HR, and MSNA. The present study demonstrated that a pressor response during water drinking was associated with the attenuation of MSNA and not generated by gastric infusion of water at the same rate as in this drinking manner. In conclusion, the rapid rise in BP might be caused through stimulations from the oropharyngeal region, swallowing-induced factors, and/or a feedforward mechanism by a central descending signal from the higher brain centers.

Background: It is warranted to test the hypothesis that the orthostatic tolerance does not diminish in the aging process per se in healthy individuals., Objective: The purpose of the present study was to examine the effects of aging on cardiovascular response and baroreflex sensitivity during lower body negative pressure (LBNP) with a special reference to leg compliance., Methods: Fifteen healthy old male subjects [mean age 68.2 +/- (SE) 0.8 years] and 22 young male subjects [mean age 21.4 +/- (SE) 0.3 years] underwent a 21-min bout of ramped LBNP (from 0 to -60 mm Hg, 10 mm Hg each for 3 min). Heart rate (HR), blood pressure, stroke volume (SV), forearm blood flow, and leg volume were measured throughout the experimental period. The arterial baroreflex sensitivity was calculated from spontaneous changes in beat-to-beat arterial pressure and HR during LBNP., Results: The leg compliance was lower, and the orthostatic tolerance index was higher in old than in young participants. The LBNP-associated increases in leg volume and HR and the decreases in SV were lower in old subjects, suggesting that the reduction of venous return was less in magnitude in old subjects during LBNP. The baseline value of baroreflex sensitivity evaluated by the sequence analysis was smaller, and no LBNP-related change was observed in old subjects, whereas a gradual LBNP-related reduction was observed in young subjects. The slope of regression between DeltaSV and change in forearm vascular resistance during LBNP was identical in both age groups., Conclusions: We conclude that: (1) aging per se does not increase the intolerance to orthostatic stress induced by LBNP; (2) a low magnitude of venous return reduction during LBNP contributes to a higher tolerance in the old because of lower leg compliance, and (3) the sensitivity of baroreflex control of the HR is attenuated in the old; however, there is no deterioration of the sensitivity of the peripheral vasoconstriction during LBNP., (Copyright 2002 S. Karger AG, Basel)

The present study was designed to test the hypothesis that sympathetic nerve activity is attenuated in a hyperbaric environment. Response of muscle sympathetic nerve activity (MSNA) to central circulatory hypovolemic stress, lower body negative pressure (LBNP), was measured in nine men at normal and at 3 atm pressures. The stress consisted of 4 min each of control and LBNP at -20 and -40 mmHg. In addition to MSNA, heart rate, stroke volume (SV), forearm blood flow (FBF), and volume of the lower leg were recorded. A reduction of baseline HR occurred with increased forearm vascular resistance at 3 atm abs. The baseline MSNA decreased during hyperbaria. MSNA increased progressively with increasing LBNP in both atmospheric pressures, and the change from the baseline (DeltaMSNA) was similar in both conditions. Changes in SV, FBF, and volume of the lower legs in response to LBNP were not statistically different during exposure to 2 atm pressures. The present study suggests that hyperbaria attenuates sympathetic nerve activity; however, its responsiveness to hypovolemic stress was not affected by hyperbaric exposure.

Purpose: An attenuated baroreflex response and orthostatic intolerance have been reported in endurance-trained male athletes; however, it is still unknown whether this occurs also in females. The purpose of the present study was to examine whether endurance exercise-trained women had a predisposition to orthostatic compromise, and if so, what causative factor(s) may induce orthostatic intolerance., Methods: We studied cardiovascular and hormonal responses to graded lower body negative pressure (LBNP) (0 to -60 mm Hg) in 26 middle-distance female runners (18.6 +/- 0.1 yr) as the exercise-trained (ET) subjects and 23 age-matched untrained (UT) control subjects. On the basis of the occurrence of syncope episodes during LBNP, ET and UT subjects were further allocated to two groups; ET with presyncope (ET+syncope) and without presyncope (ET-syncope) and UT with presyncope (UT+syncope) and without presyncope (UT-syncope)., Results: Occurrence of presyncope episodes during LBNP was higher in ET (65.4%, P < 0.05) than that for UT (34.8%). Leg compliance was higher (P < 0.05) in ET than in UT. LBNP reduced stroke volume (SV) more (P < 0.05), increased heart rate (HR) higher (P < 0.05), and increased forearm vascular resistance (FVR) more in ET+syncope as compared with the other groups. Response of vasoactive hormones to LBNP was higher in ET+syncope (P < 0.05) than that of the other groups except for norepinephrine (NE); high in both ET+syncope and UT+syncope. The relationship between SV and NE, an index of sympathetic neuronal response, had no training-related changes during LBNP., Conclusion: We conclude that exercise-trained females have a high incidence of orthostatic intolerance during LBNP, with a greater reduction of SV independent of changes in baroreflex and neurohumoral function. A lower incidence of LBNP intolerance in UT may be accounted for by a lower reduction of SV during LBNP. An increase in leg compliance in the exercise-trained females may play an important role in inducing pronounced reduction of SV and hence the intolerance to LBNP.

To investigate precisely the fluid shifts associated with water drinking in humans, we measured continuously blood density and plasma electrolyte concentrations using the mechanical oscillator technique and ion-selective electrodes, respectively, in healthy young volunteers before (10 min) and after (48 min) water drinking for a period of 2 min. Beat-by-beat blood pressure was also monitored throughout the experiment. Drinking 1 l tap water caused a transient increase in blood density immediately after the drinking episode (from 1051.1+/-0.5 g/l before drinking to 1051.8+/-0.5 g/l 4 min after the start of drinking, P<0.05), followed by a gradual reduction (1050.1+/-0.5 g/l at 31 min). This drinking-induced change paralleled those of haematocrit, plasma density and plasma volume. Plasma [Na+] and [Cl-] and osmolality decreased after drinking without transient increases and reached minima at about 30 min. A transient increase in mean arterial blood pressure was observed prior to the increase in blood density. These findings suggest that water drinking causes a biphasic change in plasma volume: initial haemoconcentration, probably due to sympathetic acceleration, followed by haemodilution due to the post-absorptive effect, and further suggest that the fluid shift associated with the initial haemoconcentration is isosmotic.

We report a case of a compound adrenal medullary tumor. A 63-year-old woman was referred to our hospital for examination of a right adrenal tumor, incidentally found by abdominal computed tomography (CT). CT and magnetic resonance imaging (MRI) revealed a round heterogeneous tumor, 5 cm in diameter, on the upper pole of the right kidney. A view of the total body scan demonstrated the uptake into the tumor after the injection of 123I-metaiodobenzyl-guanidine. Serum and urinary adrenaline levels were slightly elevated, and urinary excretion of vanillylmandelic acid was markedly elevated. Her blood pressure was normal. From these findings, the tumor was suspected to be a pheochromocytoma of the right adrenal gland and was resected reteroperitoneally. Pathological diagnosis was a compound adrenal medullary tumor, which was composed of pheochromocytoma and ganglioneuroma. This combination of the adrenal medullary tumor is extremely rare, and to date this case may be the sixth case in the Japanese medical literature.

Background: The present study was designed to examine whether water temperature during head-out immersion (HOI) modifies hemodilution dynamics., Methods: We made continuous measurements of blood density (rho(b)) during HOI at 3 different water temperatures; the lower critical (32 degrees C), neutral (34.5 degrees C), and upper critical (36 degrees C) temperatures in 6 healthy male volunteers. Blood was withdrawn continuously from the antecubital vein for measurement of rho(b) during 60 min of water immersion with a 10-min control period before the immersion. The density was measured with the mechanical oscillator technique. Hematocrit (Hct), plasma density (rho(p)), and osmolality were measured at 5-min intervals. Erythrocyte density (rho(e)) was calculated from rho(b), rho(p) and Hct. Cardiac output and BP were measured to calculate total peripheral resistance., Results: Hct, rho(b), and rho(p) decreased rapidly in the first 20-25 min of immersion and were maintained at a reduced level during immersion. Plasma volume calculated from rho(p) and Hct increased with the rho(b) reduction. These immersion-induced changes were independent of these water temperatures. Plasma osmolality and rho(e) remained constant throughout the experimental period in the three temperature conditions, indicating that the increase in plasma volume and hence hemodilution was induced by an isotonic fluid shift from extravascular space. The total peripheral resistance increased inversely in proportion to the water temperature during HOI., Conclusion: In the present condition, water temperature did not modify the net transcapillary fluid transfer during HOI in the presence of the temperature dependent increase in vascular tone.

A concise synthesis of a versatile chiral C4 building block for 2-aminoalkanols, (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammo nium benzoate (1a), was described. 1 (1a and its enantiomer 1b) acted as four stereoisomers of optically active 2-amino-1,3,4-butanetriol. The versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of 2.

Background: This study examines the relationship between the threshold for plasma vasopressin concentration [PVP] responses and diuresis (Gauer-Henry reflex), and tests the hypothesis that water intake would not influence diuresis., Methods: Eight men (19-25 yr) underwent four treatments: euhydration in air (Eu-air), euhydration in water immersion (Eu-H2O), and with prior 3.6% hypohydration in air (Hypo-air), and hypohydration in immersion (Hypo-H2O). Ad libitum drinking was allowed during the 3-h experimental and 1-h recovery periods., Results: Drinking was greatest during the first 10 min: 3.5 ml x kg(-1) with Hypo-air (450 ml x 3 h(-1)) and only 1.7 ml x kg(-1) (p < 0.05) with Hypo-H2O (235 ml x 3 h(-1)). At 1 h, concomitant [PVP] decreased from a control level of 6.6+/-1.5 to 4.0+/-1 .0 pg x ml(-1) (delta = 2.6 pg x ml(-1), p < 0.05) with Hypo-air, and from 5.9+/-0.6 to 2.3+/-0.2 pg x ml(-1) (delta = 3.6 pg x ml(-1), p < 0.05) with Hypo-H2O. Urine flow was unchanged from control level (<1.0 ml x min(-1)) with Hypo-air, Hypo-H2O, and Eu-air, but increased to 4-5 ml x min(-1) with Eu-H2O. Neither water intake volume nor urine flow was related to the magnitude of [PVP] depression. Regression of Uosm/Posm ratio on [PVP] and urine flow indicated that [PVP] above 2 pg x ml(-1) did not affect urine flow. Thus, ad libitum water intake in previously hypohydrated subjects did not affect urine flow or the decrease in [PVP]. The threshold [PVP] to initiate significant diuresis was about 2 pg x ml(-1), and significant diuresis can occur with no change in [PVP] maintained at about 1 pg x ml(-1) during immersion in euhydrated subjects., Conclusions: Thus, it appears that the Gauer-Henry reflex is not the major mechanism for immersion-induced diuresis. Clearly, other diuretic factors are also involved.

A case of resection of metastatic multiple lung malignant pheochromocytoma is presented. Seven years before, total resection of the right adrenal gland and the right kidney was performed to remove a pheochromocytoma. During the post-surgical observation in the urology outpatient clinic, the blood noradrenalin concentration increased and multiple lung metastatic nidi were observed by chest X-ray. An excision was made to remove 3 wedge-shape metastatic nidi from both lungs. In the third year after the removal of the pulmonary metastatic nidi, a resection was again performed due to recurrence in the left retroperitoneal lymph node. Another recurrence was found in the S6 liver 1 year after the removal of the lymph node, and TAE and PEIT were conducted. When the recurrent metastatic nidi were found, the blood noradrenalin concentration was elevated, and it normalized after treatment. In this case, careful and long-term observation including monitoring the blood noradrenalin concentration in the outpatient clinic and positive surgical treatment proved effective. The patient is currently in good health without signs of recurrence 12 years after the removal of the primary adrenal nidus and 6 years after the removal of the pulmonary metastatic nidus.

Background: The hydrostatic pressure gradient during head-out water immersion (HOI) causes a blood shift from the legs into the thoracic cavity to stretch the receptors in the cardiac atria and results in a diuresis in hydrated subjects. The present study was conducted to examine whether the HOI-induced diuresis and related circulatory and hormonal changes were attenuated in the subjects who had no legs (legless men)., Methods: Two legless men served as the subjects. They lost both legs 15 and 17 yr ago by accidents and were otherwise healthy. Six normal males participated as controls. The experimental protocol was consisted of a 1-h control, a 3-h HOI (water temperature, 34.5 degrees C) and a 1-h recovery., Results: Average urine flow (0.6 ml x min(-1)), urinary excretion of sodium (90 microeq x min(-1)), and osmolal clearance (1.4 ml x min(-1)) of the legless subjects increased in the first h of immersion to 0.7 ml x min(-1), 139 microeq x min(-1), and 1.8 ml x min(-1), respectively. These values remained elevated during HOI, however, the magnitude of the increase was smaller compared with the control subjects. Plasma arginine vasopressin was significantly (p < 0.05) decreased from 1.0+/-0.4 microU x 100 ml(-1) to 0.4+/-0.2 microU x 100 ml(-1) during HOI in the normal subjects, but was not in the legless subjects (from 0.5 at control period to 0.4 microU x 100 ml(-1) during HOI). A concurrent reduction of aldosterone and plasma renin activity was observed with an increase in atrial natriuretic peptide during HOI in both subject groups, however, the magnitude of the changes was smaller in the legless subjects compared with the control subjects. Similarly, the average increase in cardiac output during HOI in the legless subjects (by 17%) was less compared with the control subjects (by 31%)., Conclusion: The magnitude of renal, endocrine, and cardiovascular changes in response to HOI in the legless subjects were less than in control subjects, but the responses were qualitatively similar. Accordingly, we suggest that the cephalad blood expansion during immersion is not only due to translocation of blood from the legs but also the abdominal region.

Background: This experiment was designed to examine the involvement of the autonomic nervous system in the production of hyperbaric bradycardia., Methods: Four male divers were exposed to a He-O2 (heliox) environment at 24 atmosphere absolute (atm abs) for 7 d. The heart rate (HR) and respiratory rate were recorded at rest in the morning (0700 h) and at night (2230 h) on 1 d during a 5-d predive control, 2 d during a 7-d saturation dive at 24 atm abs, 2 d during decompression, and on 1 d during a 4-d postdive period. Cardiac sympathetic and parasympathetic activities were estimated by using a spectral analysis of the variability of R-R intervals., Results: The morning HR did not fluctuate throughout the experimental days. The night time HR decreased (p < 0.05) by 11.8% on the first day at 24 atm abs compared with that of the predive control. The bradycardia diminished gradually and returned to the predive level with continued exposure at 24 atm abs. The high-frequency power of the cardiac variability, an index of cardiac parasympathetic activity, increased (p < 0.05) only in the first night at 24 atm abs, whereas the low-frequency power and a ratio of low- to high-frequency power, an index of cardiac sympathetic activity, were unchanged., Conclusions: The present results suggest that an increased parasympathetic activity rather than a decrease in the sympathetic activity is responsible for the bradycardia on exposure to heliox dry saturation dive at 24 atm abs. The mechanism of the gradual disappearance of the bradycardia is unknown, but perhaps it may be related to the development of cardiovascular deconditioning.

Tacrolimus has already gained a high reputation as an induction-maintenance immunosuppressive therapy after kidney transplantation. Recently, it is being used as rescue therapy against rejection, and its effectiveness also appears to have been established to some extent. In this study, we evaluated the efficacy of Tacrolimus rescue therapy at 4 institutions in the Kinki District. The subjects were 19 patients treated with Tacrolimus against rejection observed during immunosuppressive therapy using cyclosporin. Evaluation was made by classifying the patients into 6 with acute rejection that occurred within 3 months after transplantation (AR), 4 with late onset acute rejection that developed more than 3 months after operation (LAR), and 9 patients with chronic rejection (CR). In the AR group, many patients received combination therapy at the introduction of Tacrolimus, and the long-term outcome was satisfactory. Tacrolimus was effective in 2 (50%) of the 4 patients in the LAR group. The trough levels of Tacrolimus at its introduction were 10-15 ng/ml in the AR and LAR groups. Deterioration of the transplanted kidney function was prevented in 3 (50%) out of 6 patients in the CR group observed for less than 1 year, but it deteriorated in all 3 patients observed for 1 year or longer. The trough levels of tacrolimus at its introduction were 5-10 ng/ml in many patients in the CR group. The rescue therapy using Tacrolimus was effective against acute rejection but further follow-up is considered to be needed to evaluate its efficacy against chronic rejection.