Effects of exercise intensity on gut microbiome composition and function in people with type 2 diabetes.

Exercise is positively associated with higher microbial diversity, but there is limited information on exercise intensity's effect on gut microbiome composition and function in clinical populations. This study examines whether different intensities of exercise exert differential effects on gut microbiome composition and function in low active people with type 2 diabetes. This is a sub-study of the Exercise for Type 2 Diabetes Study, a single centre, prospective, randomised controlled trial. Participants (n = 12) completed 8-weeks of combined aerobic and resistance moderate intensity continuous training (C-MICT) or combined aerobic and resistance high-intensity interval training (C-HIIT). Faecal samples were collected before and after intervention to measure gut microbiome composition and metabolic pathways (metagenome shotgun sequencing) and short-chain fatty acids. Post-exercise α-diversity was different between groups as was the relative abundance of specific taxa was (p < .05). Post-exercise relative abundance of Bifidobacterium, A. municiphila, and butyrate-producers Lachnospira eligens, Enterococcus spp., and Clostridium Cluster IV were higher at lower exercise intensity. Other butyrate-producers (from Eryspelothrichales and Oscillospirales), and methane producer Methanobrevibacter smithii were higher at higher exercise intensity. Pyruvate metabolism (ko00620),COG "Cell wall membrane envelope biogenesis" and "Unknown function" pathways were significantly different between groups and higher in C-MICT post-exercise. Differential abundance analysis on KO showed higher expression of Two-component system in C-HIIT. Transcription factors and "unknown metabolism" related pathways decreased in both groups. There were no significant between group changes in faecal short chain fatty acids. Exercise intensity had a distinct effect on gut microbiome abundance and metabolic function, without impacting short-chain fatty acid output.HighlightsEvidence of exercise effect on gut microbiome outcomes is limited to healthy and athletic populationsIn low active people with type 2 diabetes, different exercise intensities increased specific health promoting and butyrate producers species, and showed differentially abundant gut microbiome metabolic pathways.Further investigation is warranted, and if this supports the present findings, then specific exercise intensities may be promoted to target specific species and optimise gut health.

Critical proinflammatory role of thymic stromal lymphopoietin and its receptor in experimental autoimmune arthritis.

OBJECTIVE: The interleukin-7 (IL-7)-related cytokine thymic stromal lymphopoietin (TSLP) is a potent activator of myeloid dendritic cells, enhancing Th2-mediated hypersensitivity, and it has been implicated in the pathogenesis of atopic diseases. Although intraarticular concentrations of TSLP have been shown to be increased in patients with rheumatoid arthritis (RA), the functional capacities of TSLP in arthritis are poorly studied. The purpose of this study was to investigate the effects of TSLP administration and TSLP receptor deficiency on immune activation, arthritis severity, and tissue destruction in T cell-driven arthritis models of RA. METHODS: Immunopathology was studied in arthritic mice that were given multiple injections of murine recombinant TSLP and in mice that were deficient in the TSLP receptor (TSLPR(-/-)). Arthritis severity and incidence were determined by visual examination of the paws. Joint destruction was determined by assessing radiographs and the immunohistochemistry of ankle joints. Total cellularity and numbers of T cell subsets were assessed. Proinflammatory mediators were measured by multianalyte profiling of serum or paw protein extracts. RESULTS: Administration of TSLP significantly exacerbated the severity of collagen-induced arthritis and the joint damage that was associated with increased T cell activation. Furthermore, TSLPR(-/-) mice had less severe arthritis than did wild-type mice. TSLPR(-/-) mice had diminished concentrations of local proinflammatory and catabolic mediators, including IL-17, IL-1ß, IL-6, basic fibroblast growth factor, and matrix metalloproteinase 9, while levels of the regulatory cytokines IL-10 and IL-13 were increased. CONCLUSION: TSLP and its receptor enhance Th17-driven arthritis and tissue destruction in experimental arthritis. The increased expression of TSLP as well as the increased number of TSLPR-expressing cells in the joints of patients with RA suggest that TSLP and its receptor constitute novel therapeutic targets in RA.

Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice.

C57BL/6 mice genetically deficient in interleukin 15 (IL-15(-/-) mice) were generated by gene targeting. IL-15(-/-) mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8(+) T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15(-/-) mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15(-/-) mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15(-/-) mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15(-/-) mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15(-/-) mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

Mouse models of systemic lupus erythematosus reveal a complex pathogenesis.

The mammalian immune system is remarkable in that it can respond to an essentially infinite number of foreign antigens. The ability to mount a long-lasting (adaptive) immune response against foreign antigen requires the participation of cells selected from an enormously diverse population of B and T cells. Because the B and T cell receptors expressed by these cells are generated at random, a significant percentage of B and T cells are invariably directed against self-antigen. Under normal circumstances, autoreactive B and T cells are eliminated, reprogrammed, or inactivated in the primary and secondary lymphoid organs. Despite these checks and balances, a small but significant number of people and animals still develop autoimmune disease. One such autoimmune disease-systemic lupus erythematosus-is characterized by the loss of B- and T-cell tolerance to self-antigens (principally nuclear), culminating in multisystemic inflammation. Multiple genetic defects, drug exposure, infectious agents, and environmental factors can contribute to the pathogenesis of the disease. Loss of B- and T-cell tolerance precipitates activation of plasmacytoid and myeloid dendritic cells; collectively, these cells cooperate to form a complex positive feedback loop, continually stimulated by the persistence of self-antigen. Novel treatment strategies now focus on specific inhibition of various aspects of the feedback loop. These specific inhibitors have the potential to be more effective and lack the side effects associated with generalized immunosuppression.

Comment on "Existence of internal modes of sine-Gordon kinks".

In Phys. Rev. B 42, 2290 (1990) we used a rigorous projection operator collective variable formalism for nonlinear Klein-Gordon equations to prove the continuum sine-Gordon (SG) equation has a long lived quasimode whose frequency is in the continuum just above the lower phonon band edge with a lifetime . We confirmed the analytic calculations by simulations which agreed very closely with the analytic results. In Phys. Rev. E 62, R60 (2000) the authors performed two numerical investigation which they asserted "show that neither intrinsic internal modes nor quasimodes exist in contrast to previous results." In this paper we prove their first numerical investigation could not possibly observe the quasimode in principle and their second numerical investigation actually demonstrates the existence of the SG quasimode. Our analytic calculations and verifying simulations were performed for a stationary sine-Gordon soliton fixed at the origin. Yet the authors in Phys. Rev. E 62, R60 (2000) state the explanation of our analytic simulations and confirming simulations are due to the Doppler shift of the phonons emitted by our stationary sine-Gordon soliton which thus has a zero Doppler shift.

Double sine-Gordon ratchet induced by excitation of an internal mode.

In a recent paper [Phys. Rev. E 69, 056612 (2004)] we showed the symmetry analysis of Flach et al. [Phys. Rev. Lett. 88, 184101 (2002)] which predicted the appearance of directed energy current in homogeneously spatially extended systems described by nonlinear field equations coupled to a heat bath in the presence of a correct choice for the time dependence of an external ac field, E(t), was due to the excitation of an internal mode. Flach applied their analysis to the sine-Gordon (SG) equation and verified the symmetry breaking numerically. In the SG case we showed the internal mode coupled to the center of the mass variable, X(t), that caused the symmetry breaking was Gamma(t) the slope of the kink. We also found that the phonon dressing of the SG kink by the ac driver, chi(t), was necessary for the occurrence of a directed energy current in the SG equation. We show in the case of the double sine-Gordon (DSG) equation that the excitation of the internal mode, R(t) (where R(t) is the separation of the two subkinks that make up the DSG soliton), combined with the phonon dressing of the DSG soliton also causes a directed energy current.

UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.

OBJECTIVES: UCN-01, a novel protein kinase C inhibitor, is currently being tested in phase I clinical trials after being noted to induce apoptosis in lymphoid cell lines. We sought to study the in vitro activity of UCN-01 against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing this cytotoxicity. METHODS: Detailed in vitro studies were performed from tumor cells derived from patients with CLL cells following attainment of written informed consent. RESULTS: The 50% loss of viability (LC(50)) in mononuclear cells from CLL patients (n = 10) following exposure to UCN-01 for 4 days was 0.4 microM (95% CI +/- 0.21; range 0.09-1.16). Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.4 and 5.0 microM of UCN-01 resulted in decreased expression of p53 protein. We therefore investigated the dependence of UCN-01 on intact p53 by exposing splenocytes from wild-type (p53(+/+)) and p53 null (p53(-/-)) mice, which demonstrated no preferential cytotoxicity when compared to the marked differential induced by F-Ara-A and radiation. CONCLUSIONS: UCN-01 has significant in vitro activity against human CLL cells that appears to occur independent of p53 status. While demonstration of in vitro cytotoxicity does not establish in vivo efficacy, the findings described support the early introduction of UCN-01 into clinical trials for patients with B-CLL.

Theophylline, pentostatin (Nipent), and chlorambucil: a dose-escalation study targeting intrinsic biologic resistance mechanisms in patients with relapsed lymphoproliferative disorders.

In spite of the chemosensitivity seen with the initial treatment of malignant lymphoid disorders, relapse is common and death most often occurs as a result of disease progression. This is related to a multitude of resistance mechanisms associated with the various lymphoproliferative disorders. As a result, therapies targeting intrinsic drug-resistance mechanisms are evolving and have become an active area of research. In vitro studies of human chronic lymphocytic leukemia cells incubated with theophylline, a phosphodiesterase inhibitor, resulted in downregulation of bcl-2 concomitant with induction of apoptosis. We describe the preclinical basis for a novel combination therapy involving pentostatin (Nipent; SuperGen, San Ramon, CA), chlorambucil, and theophylline in the treatment of patients with relapsed chronic lymphoproliferative disorders. An ongoing study based on such justification, which is currently accruing patients, is also described. Results from this trial appear promising, and a phase II study is now being planned.

Application of quantitative structure-activity relationships in the development of the antiallergic pyranenamines.

QSAR techniques played a major role in development of the antiallergic pyranenamines (I). Graphical analysis of data resulting from an unsuccessful Topliss approach suggested that increased substituent hydrophilicity might enhance potency. The 3-NHAc-4-OH derivative which first resulted was an order of magnitude more potent than any preceding series member, and its deacylated congenar is clinical candidate SK&F 78729 (R1 = -NH2, R2 - OH, R3 = H). Further pursuit of hydrophilicity and other strategies suggested by multiple regression yielded 98 pyranenamines, the most active [R1 = R3 = NHCO(CHOH)2H, R2 = H] being 1000 times more potent than any original series member.

Pyranenamines: a new series of antiallergic compounds.

Condensation of 3,5-diacylpyrantriones with various aromatic amines gave a new class of potent, orally active, antiallergic compounds, the 3-[(arylamino)ethylidene]-5-acylpyrantriones, hereafter referred to as pyranenamines, as evaluated not only in the traditional rat passive cutaneous anaphylaxis (PCA) assay but also in the in vitro fragmented rat and primate lung assay. Potencies in the PCA system, when measured intravenously, reached a maximum ID50 of 0.9 mu/kg (1000 times more potent than disodium chromoglycate) with 5-acetyl-4-hydroxy-3-[1-[(3,5-bis-glyceramoylphenyl)amino]ethylidene]-2H-pyran-2,6(3H)-dione (100), as predicted by structure-activity relationship (SAR) analysis. Potencies in the iv PCA system correlated well with potencies in the in vitro rat lung system but not with potencies in the oral PCA system or the in vitro primate lung system. Several compounds had good oral potency, and one analogue, 3-acetyl-4-hydroxy-3-[1-[3-amino-4-hydroxyphenyl)amino]ethylidene]-2H-pyran-2,6(3H)-dione hydrochloride (78), reached an oral ID50 of less than 1 mg/kg and was better than 10 times more effective than disodium chromoglycate at inhibiting the release of histamine and slow-reacting substance of anaphylaxis in the fragmented primate lung assay.

Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review.

We describe a newborn boy with multiple anomalies, including bilateral split foot and an interstitial deletion of chromosome 2 (q24.2-q31.1). Four additional cases in 2 families involving similar deletions have been reported. Bilateral digital anomalies of hands and feet were seen in all 5 cases, including a wide cleft between the first and second toes, wide halluces, brachysyndactyly of the toes, and camptodactyly of the fingers. Other common manifestations have included postnatal growth and mental retardation, microcephaly, down-slanting palpebral fissures, micrognathia, and apparently low-set ears. Bilateral digital anomalies were reported in 22 of 24 cases with deletions including at least part of region 2q24-q31. Digital anomalies were not prevalent in 18 patients with deletions of chromosome 2q not overlapping 2q24-q31. 2q31.1 appears to be the common deleted segment in all cases with significant digital anomalies, which implies the existence of one or more genes involved in distal limb morphogenesis in this region. HOXD13 and EVX2, located in the proximity of 2q31, were not deleted in our patient by Southern analysis. Bilateral digital malformations of the hands and feet associated with other anomalies should be evaluated by chromosome analysis focused at the 2q24-q31 region.

Carboxyamido-triazole (CAI)--a novel "static" signal transduction inhibitor induces apoptosis in human B-cell chronic lymphocytic leukemia cells.

Signal transduction is a key mechanism by which both proliferative and apoptotic processes of B-cell chronic lymphocytic leukemia (CLL) cells are mediated. Carboxyamido-triazole (CAI) is a cytostatic signal transduction inhibitor currently being tested in phase II clinical trials. Based on this, we investigated the in vitro activity of CAI in mononuclear cell isolates from patients with B-CLL (n=11). Viability, utilizing the MTT assay, was assessed at varying concentrations (0.01-100 microM) of CAI for 4 days. The CAI concentration required for 50% inhibition of cell viability (LC50), determined by the tetrazolium dye (MTT) assay, at 4 days was 53.5 microM (range 29-74.6; 95% CI+/-14.8). Cells from 6 of 11 patients (3 of whom were clinically fludarabine refractory) had a 27 percent (range 11-43) mean decline in viability at 10 microM after a 4 day drug exposure, a concentration readily attainable in humans. To assess if loss of viability was due to apoptosis, we incubated cells from 4 additional CLL patients with media or CAI (10 microM) for 4 days. Annexin-V/propidium iodine labeling subsequently demonstrated CAI significantly (p=0.049) induces apoptosis (40.1%; 95% CI+/-18.1) as compared to media matched control cells (18.3%; 95% CI+/-11.2). These data provide evidence that CAI can induce apoptosis in human CLL cells in vitro at drug concentrations attainable in vivo. These findings justify phase II studies of CAI in patients with B-CLL.

Soliton ratchets induced by excitation of internal modes.

Recently Phys. Rev. Lett. 88, 184101 (2002)]] used a symmetry analysis to predict the appearance of directed energy current in homogeneously spatially extended systems coupled to a heat bath in the presence of an external ac field E (t). Their symmetry analysis allowed them to make the right choice of E (t) so as to obtain symmetry breaking which causes directed energy transport for systems with a nonzero topological charge. Their numerical simulations verified the existence of the directed energy current. They argued that the origin of their strong rectification in the underdamped limit is due to the excitation of internal modes and their interaction with the translational kink motion. The internal mode mechanism as a cause of current rectification was also proposed by Salerno and Zolotaryuk [Phys. Rev. E. 65, 056603 (2002)]]. We use a rigorous collective variable for nonlinear Klein-Gordon equations to prove that the rectification of the current is due to the excitation of an internal mode Gamma (t), which describes the oscillation of the slope of the kink, and due to a dressing of the bare kink by the ac driver. The internal mode Gamma (t) is excited by its interaction with the center of mass of the kink, X (t), which is accelerated by E (t). The external field E (t) also causes the kink to be dressed. We derive the expressions for the dressing and numerically solve the equations of motion for Gamma (t), X (t), and the momentum P (t), which enable us to obtain the explicit expressions for the directed energy current and the ac driven kink profile. We then show that the directed energy current vanishes unless the slope Gamma (t) is a dynamical variable and the kink is dressed by the ac driver.

The future of allied health in the health promotion/disease prevention movement.

Although allied health was not included in the earliest stages of the health promotion/disease prevention movement, it now has a unique opportunity to assume a leadership position. To a great extent, realization of that potential will depend on the individual and collective efforts of the American Society of Allied Health Professions (ASAHP) and its constituencies, allied health educational institutions, professional associations, and individual professionals.

Ultrahigh-resolution spectroscopy and frequency standards in the microwave and far-infrared regions using optical lasers.

Optically induced resonance Raman transitions in atomic and molecular beams are proposed as a means of achieving ultrahigh resolution in the microwave and far-infrared regions. Line broadening that is due to laser jitter is eliminated by correlating the frequency jitter of the two optical fields inducing the Raman transition. A Ramanseparated oscillatory-field technique for reducing transit-time broadening is considered.

Lidocaine plasma concentrations following administration of intraoral lidocaine solution.

Seventeen healthy male volunteers received 15 mL of 2% solution (300 mg) of lidocaine hydrochloride every three hours for eight consecutive doses. Modes of administration were as follows: (A) each dose washed throughout the oral cavity, then spit out without swallowing; (B) each dose washed, then swallowed; and (C) each dose swallowed directly. Plasma levels of lidocaine and its two metabolites (monoethylglycinexylidide [MEGX] and glycinexylidide [GX]) were measured during and after the period of dosage. In trial A, levels of all three compounds were very low, in no case exceeding 0.3 microgram/mL. During trial C, the mean peak levels of lidocaine and MEGX, respectively, were 0.5 and 0.6 microgram/mL after the first dose, and 0.8 and 1.3 microgram/mL after the eighth dose. Both compounds were essentially undetectable by 12 hours after the last dose. Levels in trial B were very similar to those in trial C. Thus, recommended topical oral cavity use of 2% lidocaine leads to negligible systemic levels of lidocaine and metabolites. Even when doses are swallowed, systemic levels do not approach a toxic range.

The role of parietal cortex in verbal working memory.

Neuroimaging studies of normal subjects and studies of patients with focal lesions implicate regions of parietal cortex in verbal working memory (VWM), yet the precise role of parietal cortex in VWM remains unclear. Some evidence (; ) suggests that the parietal cortex mediates the storage of verbal information, but these studies and most previous ones included encoding and retrieval processes as well as storage and rehearsal of verbal information. A recent positron emission tomography (PET) study by isolated storage and rehearsal from other VWM processes and did not find reliable activation in parietal cortex. This result suggests that parietal cortex may not be involved in VWM storage, contrary to previous proposals. However, we report two behavioral studies indicating that some of the verbal material used by may not have required phonological representations in VWM. In addition, we report a PET study that isolated VWM encoding, retrieval, and storage and rehearsal processes in different PET scans and used material likely to require phonological codes in VWM. After subtraction of appropriate controls, the encoding condition revealed no reliable activations; the retrieval condition revealed reliable activations in dorsolateral prefrontal, anterior cingulate, posterior parietal, and extrastriate cortices, and the storage condition revealed reliable activations in dorsolateral prefrontal, inferior frontal, premotor, and posterior parietal cortices, as well as cerebellum. These results suggest that parietal regions are part of a network of brain areas that mediate the short-term storage and retrieval of phonologically coded verbal material.