The adaptive response of humans to exercise: Impact of exercise intensity, fibre-type specific responses and molecular patterns of response

In an attempt to improve the current understanding of the adaptive response to exercise in humans, this dissertation performed a series of studies designed to examine the impact of training intensity and mode on aerobic capacity and performance, fibre-type specific adaptations to training, and individual patterns of response across molecular, morphological and genetic factors. Project #1 determined that training intensity, session dose, baseline VO2max and total training volume do not influence the magnitude of change in VO2max by performing a meta-regression, and meta-analysis of 28 different studies. The intensity of training had no effect on the magnitude of increase in maximal oxygen uptake in young healthy participants, but similar adaptations were achieved with lower training doses following high intensity training. Project # 2 determined the acute molecular response, and training-induced adaptations in aerobic performance, aerobic capacity and muscle phenotype following high-intensity interval training (HIT) or endurance exercise (END). The acute molecular response (fibre recruitment and signal activation) and training-induced adaptations in aerobic capacity, aerobic performance, and muscle phenotype were similar following HIT and END. Project # 3 examined the impact of baseline muscle morphology and molecular characteristics on the training response, and if muscle adaptations are coordinated. The muscle phenotype of individuals who experience the largest improvements (high responders) were lower before training for some muscle characteristics and molecular adaptations were coordinated within individual participants. Project # 4 examined the impact of 2 different intensities of HIT on the expression of nuclear and mitochondrial encoded genes targeted by PGC-1α. A systematic upregulation of nuclear and mitochondrial encoded genes was not present in the early recovery period following acute HIT, but the expression of mitochondrial genes were coordinated at an individual level. Collectively, results from the current dissertation contribute to our understanding of the molecular mechanisms influencing skeletal muscle and whole-body adaptive responses to acute exercise and training in humans.

Bone fragility as a possible complication of chronic kidney disease in early stages

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Ferroportin Disease (Haemochromatosis-type IV): a case report

Introdution: Haemochromatosis-type IV, the ferroportin disease, is characterized by an autosomal-dominant transmission and early iron accumulation in macrophages. It is caused by mutations in the transmembrane iron exporter protein ferroportin1 (SLC40A1 gene). In form A (classic), ferroportin loss of function mutants are unable to export iron from cells leading to cellular iron accumulation with decreased availability of iron for serum transferrin (TS). We present a Portuguese rare clinical case of HH-IV. Materials and Methods: A 41-year-old woman with hyperferritinemia and normal TS. Causes of hyperferritinemia (inflammation, chronic alcohol consumption, metabolic syndrome, cell necrosis, non-alcoholic fatty liver disease and aceruloplasminemia) were assessed. Liver iron, evaluated by magnetic resonance imaging (MRI) was carried out. Screening for mutation in HFE and SCL40A1 genes were performed by Sanger sequencing. Baseline: Ferritin:708ng/ml; TS: 27%; MRI:85µmol/g; Hb:13,6g/dl. Therapy: weekly 450ml Therapeutic Phlebotomies (TP) until ferritin≤50ng/ml. Results: Hyperferritinemia comorbidities and common genetic mutations for haemochromatosis were negative. However, sequencing of the patient SLC40A1 gene has revealed the presence in heterozygosity of the variant c.238G>A; p.Gly80Ser. Due to low tolerance to TP, we adopted smaller phlebotomies every three weeks. Conclusion: This patient has a rare autosomal-dominant Ferroportin disease due to a mutated ferroportin which is predicted to be defective in iron cellular export. In agreement, she presents hyperferritinemia, with normal TS and liver iron overload. The genotype/phenotype association allowed to diagnosis this rare FD case. Although a mild form A, we decided to start TP. Her father also has been treated for iron overload.

Mice deficient in interleukin-4 (IL-4) or IL-4 receptor alpha have higher resistance to sporozoite infection with Plasmodium berghei (ANKA) than do naive wild-type mice

BALB/c interleukin-4 (IL-4(-/-)) or IL-4 receptor-alpha (IL-4ralpha(-/-)) knockout (KO) mice were used to assess the roles of the IL-4 and IL-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. Intraperitoneal infection with the blood-stage erythrocytes of Plasmodium berghei (ANKA) resulted in 100% mortality within 24 days in BALB/c mice, as well as in the mutant mouse strains. However, when infected intravenously with the sporozoite liver stage, 60 to 80% of IL-4(-/-) and IL-4ralpha(-/-) mice survived, whereas all BALB/c mice succumbed with high parasitemia. Compared to infected BALB/c controls, the surviving KO mice showed increased NK cell numbers and expression of inducible nitric oxide synthase (iNOS) in the liver and were able to eliminate parasites early during infection. In vivo blockade of NO resulted in 100% mortality of sporozoite-infected KO mice. In vivo depletion of NK cells also resulted in 80 to 100% mortality, with a significant reduction in gamma interferon (IFN-gamma) production in the liver. These results suggest that IFN-gamma-producing NK cells are critical in host resistance against the sporozoite liver stage by inducing NO production, an effective killing effector molecule against Plasmodium. The absence of IL-4-mediated functions increases the protective innate immune mechanism identified above, which results in immunity against P. berghei infection in these mice, with no major role for IL-13.

Stable oxygen isotope ratios of benthic and planktonic foraminifera from early Miocene sediments of DSDP Site 90-593 on the Challenger Plateau, Pacific Ocean (Table 1)

Oxygen isotope data are compared with relative abundances of selected planktic foraminifera through a ca. 15 m interval at DSDP Site 593 (Tasman Sea, southwest Pacific, 40°S) in which there are prominent changes in population sizes, as well as several evolutionary events. We focus on the relation between faunal and climatic histories. The base of early Miocene oxygen isotope Zone Mi1b (uppermost planktic foraminiferal Zone N.6) is identified from closesampled (c. 14 kyr) isotope records of Globigerina woodi and Cibicides kullenbergi. Chronostratigraphic interpolations, using the first occurrences of Globorotalia praescitula, G. mimea and Praeorbulina curva give an age estimate of ca. 18.4 Ma (cf. 18.1 -18.3 Ma for the base of the zone at DSDP Site 608 (type level, north Atlantic, 43°N) ). Another significant benthic delta18O enrichment event, informally designated as the base of zone "Mi1c", is identified 10 m higher in the sequence at ca. 17.8 Ma. Populations of Globoquadriau dehiscens and Globigerinoides trilobus (inferred to be near the southern margin of their distributions) either reduced considerably or withdrew, particularly in the vicinity of zone "Mi1c". A bioseries linking Globorotalia incognita with G. zealandica developed following the benthic delta18O enrichment spike at the base of Zone Mi1b; the latter species became extinct (at least regionally) just above the base of zone "Mi1c". In contrast, the apparently opportunistic Globorotlia praescitula increased dramatically in abundance at this time; there were also transformations in its architecture, leading to the evolutionary appearance of G. miozea. While planktic foraminifera abundances often do not closely covary with the detailed isotope records and tend to be more stable through time, the near coincidence of evolutionary and biogeographic events with isotopic events suggests at least indirect adaptive responses to climatic changes. Early Miocene middle-latitude planktic foraminiferal evolution, biogeography, and biostratigraphy, may be intimately connected with climatic history.

Early Cretaceous planktonic foraminifera from the Tethys

Early Cretaceous planktonic foraminiferal assemblages include rare planispiral and pseudoplanispiral morphotypes with elongate chambers that BouDagher-Fadel et al. assigned to Schackoina or accommodated in the new genus Claviblowiella. New findings of well-preserved planktonic foraminiferal faunas from the Lesches en Diois (SE France) section, the Cismon core (NE Italy), the Calabianca (NW Sicily) section and the Upper Aptian of Deep Sea Drilling Project (DSDP) Site 545 drilled off Morocco, have allowed a better understanding of the morphological features of these rare, unevenly distributed taxa. Our data demonstrate that each small planispiral species with globular chambers has a corresponding "clavate" morphotype which (as the "normal" forms) exhibits a smooth, finely perforate wall. Consequently, the latter have been assigned here to the genus Globigerinelloides and treated as subspecies of the "non-clavate" taxa. The (clavate) subspecies belonging to the genus Globigerinelloides here retained are G. duboisi sigali Longoria, G. maridalensis elongatus subsp. nov., G. blowi lobatus subsp. nov. and G. paragottisi clavatus subsp. nov., while Globigerinelloides minai Obregòn de la Parra is not retained. In addition, a new genus, Pseudoschackoina, type species Planomalina saundersi Bolli (senior synonym of Hastigerinoides cepedai Obregòn de la Parra, has been formalised for individuals possessing elongate, pointed, laterally compressed chambers, bearing tubulospines arranged on a pseudoplanispiral (dysaxial) coiling mode. Stratigraphically, in the sections studied the first taxon to appear is Pseudoschackoina saundersi, in the uppermost part of the Selli Level (=OAE1a), immediately followed, just above the OAE1a, by all the "clavate" globigerinelloidids. Regarding the last occurrences, Pseudoschackoina saundersi and G. maridalensis elongatus disappear in the lower part of the Globigerinelloides algerianus Zone, Globigerinelloides paragottisi clavatus at the top of the same zone, while Globigerinelloides blowi lobatus and G. duboisi sigali range up to the lower part of the Ticinella bejaouaensis Zone.

[Calligraphic specimen, early to mid 18th century].

Exquisite album of calligraphy (muraqqaʻ or murakkaa) comprising kıt'alar employing ḥadīth of the Prophet executed by the celebrated Ottoman calligrapher Eğrikapılı Mehmet Râsim Efendi (d.1756), renowned student of Seyyid Abdullah of Yedikule (d.1731).

Orbits of the double stars, A B of [Epsilon] Hydrae and ? 883, by the graphical method.

Type-written ms.

The new American practical navigator : being an epitome of navigation; containing all the tables necessary to be used with the nautical almanac, in determining the latitude, and the longitude by lunar observations, and keeping a complete reckoning at sea; illustrated by proper rules and examples ... dictionary of sea terms; and the manner of performing the most useful evolutions at sea: : with an appendix, containing methods of calculating eclipses of the sun and moon, and occultations of the fixed stars ... /

Three pages at end contain a publishers' advertisement.

The relationship between diurnal type and time duration estimation at morning and evening times of day

This study investigates whether different diurnal types (morning versus evening) differ in their estimation of time duration at different times of the day. Given that the performance of morning and evening types is typically best at their preferred times of day, and assuming different diurnal trends in subjective alertness (arousal?) for morning and evening types, and adopting the attentional gate model of time duration estimation, it was predicted that morning types would tend to underestimate and be more accurate in the morning compared to evening types where the opposite pattern was expected. Nineteen morning types, 18 evening types and 18 intermediate types were drawn from a large sample (N=1175) of undergraduates administered the Early/Late Preference Scale. Groups performed a time duration estimation task using the production method for estimating 20-s unfilled intervals at two times of day: 0800/1830. The median absolute error, median directional error and frequency of under- and overestimation were analysed using repeated-measures ANOVA. While all differences were statistically non-significant, the following trends were observed: morning types performed better than evening types; participants overestimated in the morning and underestimated in the evening; and participants were more accurate later in the day. It was concluded that the trends are inconsistent with a relationship between subjective alertness and time duration estimation but consistent with a possible relationship between time duration estimation and diurnal body temperature fluctuations. (C) 2002 Elsevier Ltd. All rights reserved.

Effector ExoU from the type III secretion system is an important modulator of gene expression in lung epithelial cells in response to Pseudomonas aeruginosa infection

Pseudomonas aeruginosa is an important pathogen in immunocompromised patients and secretes a diverse set of virulence factors that aid colonization and influence host cell defenses. An important early step in the establishment of infection is the production of type III-secreted effectors translocated into host cells by the bacteria. We used cDNA microarrays to compare the transcriptomic response of lung epithelial cells to P. aeruginosa mutants defective in type IV pili, the type III secretion apparatus, or in the production of specific type III-secreted effectors. Of the 18,000 cDNA clones analyzed, 55 were induced or repressed after 4 It of infection and could be classified into four different expression patterns. These include (i) host genes that are induced or repressed in a type III secretion-independent manner (32 clones), (ii) host genes induced specifically by ExoU (20 clones), and (iii) host genes induced in an ExoU-independent but type III secretion dependent manner (3 clones). In particular, ExoU was essential for the expression of immediate-early response genes, including the transcription factor c-Fos. ExoU-dependent gene expression was mediated in part by early and transient activation of the AN transcription factor complex. In conclusion, the present study provides a detailed insight into the response of epithelial cells to infection and indicates the significant role played by the type III virulence mechanism in the initial host response.

Response of B-type natriuretic pepticle to exercise in hypertensive patients with suspected diastolic heart failure: Correlation with cardiac function, hemodynamics, and workload

Background Diastolic heart failure (DHF) is characterized by dyspnea due to increased left ventricular (LV) filling pressures during stress. We sought the relationship of exercise-induced increases in B-type natriuretic peptide (BNP) to LV filling pressures and parameters of cardiovascular performance in suspected DHF. Methods Twenty-six treated hypertensive patients with suspected DHF (exertional dyspnea, LV ejection fraction >50%, and diastolic dysfunction) underwent maximal exercise echocardiography using the Bruce protocol. BNP, transmitral Doppler, and tissue Doppler for systolic (So) and early (Ea) and late (Aa) diastolic mitral annular velocities were obtained at rest and peak stress. LV filling pressures were estimated with E/Ea ratios. Results Resting BNP correlated with resting pulse pressure (r=0.45, P=0.02). Maximal exercise performance (4.6 +/- 2.5min) was limited by dyspnea. Blood pressure increased with exercise (from 143 +/- 19/88 +/- 8 to 191 +/- 22/90 +/- 10 mm Hg); 13 patients (50%) had a hypertensive response. Peak exercise BNP correlated with peak transmitral E velocity (r = 0.41, P <.05) and peak heart rate (r = -0.40, P <.05). BNP increased with exercise (from 48 57 to 74 97 pg/mL, P =.007), and the increment of BNP with exercise was associated with maximal workload and peak exercise So, Ea, and Aa (P <.01 for all). Filling pressures, approximated by lateral E/Ea ratio, increased with exercise (7.7 +/- 2.0 to 10.0 +/- 4.8, P <.01). BNP was higher in patients with possibly elevated filling pressures at peak exercise (E/Ea >10) compared to those with normal pressures (123 +/- 124 vs 45 +/- 71 pg/mL, P =.027). Conclusions Augmentation of BNP with exercise in hypertensive patients with suspected DHF is associated with better exercise capacity, LV systolic and diastolic function, and left atrial function. Peak exercise BNP levels may identify exercise-induced elevation of filling pressures in DHF.

Early-Middle Jurassic stratigraphy of the Fortrose-Chaslands region, southernmost South Island, New Zealand

The 40 km of coastline from Fortrose to Chaslands Mistake (southeastern South Island, New Zealand) comprises sediments that are part of the Early-Middle Jurassic of the Murihiku Terrane. The sediments are dominantly fluvial with some marine beds and alluvial fan deposition, and display an evolution of fluvial style which progresses from perennial flow to seasonal flow. The McPhee Cove Conglomerate is a prominent unit to the north. It has been used to separate two formations which would otherwise, on inherent lithological grounds, be difficult to distinguish. This paper discusses several similar conglomerates which occur in the south, but which are separated from the type area of the McPhee Conglomerate by major tectonic disruption. Hence, the existing lithostratigraphic nomenclature to the north, including the McPhee Cove Conglomerate, cannot be simply extended southwards. The Fortrose-Chaslands area appears to consist of two tectonic blocks, the Slope Point Block and the Brothers Block, which are separated from each other and from the adjacent Papatowai Block by major strike faults (or fault zones). A change is proposed to the existing stratigraphy which involves recognising all terrestrial sediments as part of the False Island Formation. Four prominent clast-supported conglomerate horizons are named as members of the False Islet Formation: the White Head Conglomerate, Black Bluff Conglomerate. Hoiho Conglomerate, and Slope Point Conglomerate Members. The latter contains five named conglomerate beds.

Investigation of the immunocompetent cells that bind early pregnancy factor and preliminary studies of the early pregnancy factor target molecule

Early pregnancy factor (EPF) is a secreted protein with immunosuppressive and growth factor properties. It has been shown to suppress the delayed-type hypersensitivity response in mice as well as acute and chronic forms of experimental autommume encephalomyelitis in rats and mice, respectively. In previous studies, we have demonstrated that EPF binds to a population of lymphocytes and we hypothesized that it mediates its suppressive effects by binding to CD4(+) T cells. In the present study, we isolated monocytes and subpopulations of lymphocytes and labelled them with fluoresceinated EPF in order to determine which populations bind EPF. We demonstrated that EPF binds specifically to CD4(+), CD8(+), CD14(+) (monocytes) and CD56(+) NK cells but not to CD19(+) B cells. The identity of the molecule(s) on the cell surface that is targeted by EPF is unknown, but as EPF is an extracellular homologue of the intracellular protein chaperonin 10 (Cpn 10), we examined the possibility that the EPF receptor is a membrane-associated form of chaperonin 60 (Cpn60), the functional associate of Cpn 10 within the cell. The EPF target molecule on lymphocytes was visualized by chemical cross-linking of exogenous iodinated Cpn10 to cells and probed with anti-Cpn60. The effect of anti-Cpn60 on activity in the EPF bioassay, the rosette inhibition test, was also examined. In both instances, no specific interaction of this antibody and the putative receptor was observed. It was concluded that the cell surface molecule targeted by EPF is unlikely to be a homologue of Cpn60.