Impact of aerobic fitness on cerebral blood flow and cerebral vascular responsiveness to CO2 in young and older men.

We sought to test the hypothesis that brain blood flow and cerebral vascular responsiveness to carbon dioxide (CVRCO2 ) are greater in aerobically trained young and old individuals compared to their untrained counterparts. In 11 young trained {[23 (20-26) years] [mean (95% confidence interval)]}, 10 young untrained [25 (22-28) years], 8 older trained [65 (61-69) years], and 9 older untrained [67 (64-71) years] healthy individuals, Doppler ultrasound of the internal carotid (ICA) and vertebral (VA) artery blood flow were determined, along with middle cerebral artery mean flow velocity (MCA Vmean ). Bilateral ICA blood flow was higher in trained individuals when compared to untrained (≈31%, P < 0.05), but was not influenced by age. VA blood flow was not affected by age or cardiorespiratory fitness. MCA Vmean was reduced with age [59.5 (55.0-64.1) cm/s young vs 43.6 (38.4-48.9) cm/s old, P < 0.05] with no significant effect of training observed. MCA CVRCO2 were not significantly affected by either age or training status, while ICA CVRCO2 tended to be elevated in the old trained group. These findings indicate that endurance training enhances bilateral ICA but not VA blood flow in both young and older individuals.

Restoring heat stress-associated reduction in middle cerebral artery velocity does not reduce fatigue in the heat.

Heat-induced hyperventilation may reduce PaCO2 and thereby cerebral perfusion and oxygenation and in turn exercise performance. To test this hypothesis, eight volunteers completed three incremental exercise tests to exhaustion: (a) 18 °C ambient temperature (CON); (b) 38 °C (HEAT); and (c) 38 °C with addition of CO2 to inspiration to prevent the hyperventilation-induced reduction in PaCO2 (HEAT + CO2 ). In HEAT and HEAT + CO2 , rectal temperature was elevated prior to the exercise tests by means of hot water submersion and was higher (P < 0.05) than in CON. Compared with CON, ventilation was elevated (P < 0.01), and hence, PaCO2 reduced in HEAT. This caused a reduction (P < 0.05) in mean cerebral artery velocity (MCAvmean ) from 68.6 ± 15.5 to 53.9 ± 10.0 cm/s, which was completely restored in HEAT + CO2 (68.8 ± 5.8 cm/s). Cerebral oxygenation followed a similar pattern. V ˙ O 2   m a x was 4.6 ± 0.1 L/min in CON and decreased (P < 0.05) to 4.1 ± 0.2 L/min in HEAT and remained reduced in HEAT + CO2 (4.1 ± 0.2 L/min). Despite normalization of MCAvmean and cerebral oxygenation in HEAT + CO2 , this did not improve exercise performance, and thus, the reduced MCAvmean in HEAT does not seem to limit exercise performance.

Clinical Characteristics and Mortality of Old and Very Old Patients Hospitalized for Hip Fracture or Acute Medical Conditions.

BACKGROUND: There is increasing interest in healthcare quality and economic implications for hip fracture patients of very old age. However, results are limited by access to comparable control groups. OBJECTIVES: We examined healthcare quality measures including mortality and length of stay (LOS) in hospital of adults aged 60-107 years undergoing hip operations, compared to an age-matched group admitted for acute general medical conditions. DESIGN: Monocentric cross-sectional study. SETTING: Ashford and St Peter's Hospitals NHS Foundation Trust, Surrey, United Kingdom. PARTICIPANTS: A total of 3972 consecutive admissions for hip operation from 1st April 2009 to 30th June 2019 (dataset-1) and 6979 for acute general medical conditions from 1st April 2019 to 29th February 2020 (dataset-2). Respective ages, mean (±standard deviation), were 83.5 years (±9.1) and 79.8 years (±9.8). MEASUREMENTS: Mortality and LOS were assessed with each group divided into five- year age bands and those ≥95 years. RESULTS: There were proportionally more (P <0.001) females admitted for hip operations (72.8%) than for acute general medical conditions (53.8%). Amongst patients admitted with general medical conditions, the frequency of the most serious recorded conditions - including congestive heart failure, stroke, and pneumonia - increased with age. Amongst patients undergoing hip operations, 5.7% died in hospital and 29.3% had a LOS ≥3 weeks. Corresponding values for acute general medical conditions were 10.4% and 11.8%. For those undergoing hip operations in all age categories, the risk of death was lower than for acute general medical group: sex-adjusted odds ratios ranged between 0.27 and 0.67, but the risk of LOS ≥3 weeks was greater: odds ratios ranged between 2.46 and 2.95. CONCLUSIONS: Compared to those admitted with acute general medical conditions, patients admitted for hip operations had a lower risk of death, but a longer hospital LOS. .

Physical studies of phospholipids. 3. Electron microscope studies of some pure fully saturated 2,3-diacyl-DL-phosphatidyl-ethanolamines and phosphatidyl-cholines.

On heating pure, fully saturated 2,3-diacyl-DL-phosphatidyl-ethanolamines and 2,3-diacylphosphatidyl-cholines (lecithins) in water to the transition temperature at which large endothermic heat changes occur, they are observed, by light microscopy, to form myelin figures. This result is discussed in terms of the large difference in the transition temperature for "melting" of the hydrocarbon chains of unsaturated and saturated phospholipids and is illustrated by means of differential thermal analysis (D.T.A.) curves. These structures have been examined by electron microscopy after negative staining and after reaction with osmium tetroxide. Typical phospholipid lamella structures are seen in the phosphatidylcholines after negative staining, and in the phosphatidyl-ethanolamines after both negative staining and osmium fixation. The distances across these lamellae have been measured. Some preliminary investigations of the nature of the osmium tetroxide reaction with the phosphatidyl-ethanolamines have been made.

[Identification of VHL-associated changes in clear cell renal carcinoma: the application of combined genome and expression analyses]. / Identifizierung VHL-assoziierter Veränderungen im klarzelligen Nierenzellkarzinom: Anwendung von kombinierten Genom- und Expressionsanalysen.

Sporadic renal cell carcinoma (RCC) represents a heterogeneous tumor, which is traditionally classified into subtypes based on morphological criteria. In recent years high-throughput molecular analyses have been able to identify genomic and proteomic alterations in tumor cells. These markers are the basis for a molecular classification of RCC and bear prognostic value. However, an isolated consideration of genomic and proteomic alterations prevents deeper insights into the complex processes of carcinogenesis. Here we summarize recent studies focussing on this aspect of RCC and present a systems biology concept for the identification of novel tumor markers. These could be applied to improve future diagnosis and therapy of RCC.

Immunophenotyping without antibodies. New perspectives for lymphoma characterization.

AIMS: Accurate classification of haematological malignancies is a prerequisite for their correct diagnosis, prognosis and therapy. Clear classification of lymphomas is often hindered by the limited number of available cell surface protein markers that are suitable for immunophenotyping. A systematic and quantitative analysis of cell surface proteins is thus required to identify new protein markers on lymphoma subtypes in an unbiased and discovery-driven approach. METHODS: Nine Hodgkin and non-Hodgkin B cell lines of diffuse large cell type and mediastinal type were investigated by cell surface capture (CSC) technology, a mass spectrometry-based method to identify cell surface glycoproteins. Selected proteins are verified by antibody-based methods, including flow cytometry and immunohistochemistry on cell line arrays. RESULTS: A total of 747 predicted transmembrane proteins were identified from all cell lines, including 142 CD (cluster of differentiation) annotated proteins. A group of differentially expressed cell surface glycoproteins between Hodgkin and non-Hodgkin B cell lines was revealed via quantitative CSC technology. In addition to classical and expected CD molecules such as CD20 and CD30, less frequently expressed molecules such as CD2 on Hodgkin lymphoma (HL) cell lines were identified by CSC and verified by immunohistochemistry in cell lines and primary lymphoma tissue. A panel of CSC-identified differentiation glycoprotein candidates is currently under investigation on tissue microarrays (TMAs) from patient samples.

Exercise training increases skeletal muscle mitochondrial volume density by enlargement of existing mitochondria and not de novo biogenesis.

AIMS: (i) To determine whether exercise-induced increases in muscle mitochondrial volume density (MitoVD ) are related to enlargement of existing mitochondria or de novo biogenesis and (ii) to establish whether measures of mitochondrial-specific enzymatic activities are valid biomarkers for exercise-induced increases in MitoVD . METHOD: Skeletal muscle samples were collected from 21 healthy males prior to and following 6 weeks of endurance training. Transmission electron microscopy was used for the estimation of mitochondrial densities and profiles. Biochemical assays, western blotting and high-resolution respirometry were applied to detect changes in specific mitochondrial functions. RESULT: MitoVD increased with 55 ± 9% (P < 0.001), whereas the number of mitochondrial profiles per area of skeletal muscle remained unchanged following training. Citrate synthase activity (CS) increased (44 ± 12%, P < 0.001); however, there were no functional changes in oxidative phosphorylation capacity (OXPHOS, CI+IIP ) or cytochrome c oxidase (COX) activity. Correlations were found between MitoVD and CS (P = 0.01; r = 0.58), OXPHOS, CI+CIIP (P = 0.01; R = 0.58) and COX (P = 0.02; R = 0.52) before training; after training, a correlation was found between MitoVD and CS activity only (P = 0.04; R = 0.49). Intrinsic respiratory capacities decreased (P < 0.05) with training when respiration was normalized to MitoVD. This was not the case when normalized to CS activity although the percentage change was comparable. CONCLUSIONS: MitoVD was increased by inducing mitochondrial enlargement rather than de novo biogenesis. CS activity may be appropriate to track training-induced changes in MitoVD.

Myocardial tissue perfusion determined by particulate and diffusible tracers during ischaemia: what is measured?

OBJECTIVE: Myocardial perfusion can be determined by many techniques which can be broadly divided into those employing particulate tracers and those employing diffusible tracers. The most commonly used particulate tracer is radioactive microspheres. However, as with other particulate tracers, they only determine convective transport from pre-capillary arterioles. If convective transport is the limiting factor in solute exchange, then particulate tracers will give comparable measurements to diffusible tracer techniques. However, if solute transport becomes diffusion-limited or alternative pathways of convective transport become more important, which may occur during regional ischaemia, perfusion visualised with clearance techniques using diffusible tracers may be greater than that determined with particulate tracers. This study set out to investigate this possibility in the rabbit myocardium under normal and ischaemic conditions. METHODS: A pentobarbitone-anaesthetised rabbit model of regional ischaemia was used. Ischaemia of the apical region was induced by ligation of the large left ventricular branch of the circumflex artery. Tissue perfusion was determined by radioactive microspheres (n = 5) and the clearance of hydrogen, which was detected voltammetrically by platinum microelectrodes (n = 5). Measurements were made prior to and following coronary ligation and the ischaemic region was demarcated using the particulate tracer monastral blue. The exchange of diffusible solutes was visualised using digital fluorescence microscopy on histological sections of tissue following systemic administration of the fluorophore Evans blue labelled albumin (n = 4). RESULTS: Coronary ligation produced an ischaemic zone occupying 50 +/- 13% of the left ventricle. In ischaemic tissue, flow determined by microspheres fell to 3.9 +/- 4.1% of its pre-ligation value, but solute exchange fell only to 22 +/- 10% (adjusted for changes in the partition coefficient of H2 during ischaemia, P < 0.05). Perfusion measured by microspheres and hydrogen clearance was unchanged in the non-ischaemic area during coronary ligation. There was preferential uptake of Evans blue albumin towards the endocardial surface in the ischaemic region and areas of local uptake through the ventricular wall, which were possibly associated with vessels. CONCLUSION: This work demonstrates that under normal physiological conditions nutrient supply is determined by pre-capillary delivery. However, during ischaemia diffusive transport plays an increasingly important role. The alternative pathways for solute exchange are likely to have an important influence on the rate and extent of myocardial necrosis during coronary occlusion.

Effects of the PAF antagonists BN50726 and BN50739 on arrhythmogenesis and extent of necrosis during myocardial ischaemia/reperfusion in rabbits.

1. The effects of two novel platelet activating factor (PAF) antagonists BN50726 and BN50739 on arrhythmias, haemodynamics and extent of necrosis during myocardial ischaemia and reperfusion were investigated in anaesthetized rabbits subjected to coronary artery ligation. 2. BN50739 reduced heart rate prior to coronary artery occlusion (P < 0.005) but had no other significant haemodynamic effects at this time. BN50739 and BN50726 did not significantly alter heart rate or blood pressure during 30 min of ischaemia or 30 min of reperfusion, compared to control hearts. 3. BN50739 and BN50726 had no effect on the incidence of arrhythmias during ischaemia. BN50726 significantly reduced the incidence of reperfusion ventricular fibrillation compared to controls (0% v 40%, P < 0.05), and improved survival (80% v 39%, P < 0.05). Similar trends were observed with BN50739. 4. BN50726 reduced the extent of necrosis compared to control hearts (18 +/- 2% v 30 +/- 3%, P < 0.01). A similar trend was observed with BN50739. 5. These results demonstrate that PAF antagonism with BN50726 attenuates reperfusion-induced arrhythmias and preserves myocardium in the early phase of ischaemia, independently of haemodynamic effects.

Effects of cicletanine on haemodynamics, arrhythmias and extent of necrosis during coronary ligation in rabbits.

1. The effects of cicletanine on arrhythmias, haemodynamics and extent of necrosis during myocardial ischaemia were investigated in rabbits subjected to coronary ligation. 2. Cicletanine increased cardiac output prior to coronary occlusion (P < 0.01) but had no other significant haemodynamic effects at this time and did not significantly alter heart rate, blood pressure or cardiac output during 30 min of ischaemia or 30 min of reperfusion. 3. Ventricular fibrillation and mortality were greater in control (65% and 60% respectively) than treated animals (15.4% and 15.4%, P < 0.01). 4. The extent of myocardial necrosis expressed as a percentage of the area at risk was also reduced by cicletanine from 61 +/- 8% in controls to 37 +/- 6% (P < 0.05). 5. These findings indicate that cicletanine attenuates arrhythmias and preserves myocardium in the early phase of ischaemia and this effect appears to be independent of an established antihypertensive action.

Campylobacter myocarditis; loose bowels and a baggy heart.

We report an unusual case of acute myocarditis associated with Campylobacter jejuni enterocolitis leading to severe impairment of left ventricular systolic function. Contrast-enhanced cardiac magnetic resonance imaging was used to confirm the presence of acute myocardial inflammation and its resolution.

Tropical myositis: ultrastructural studies.

Specimens of muscle were obtained from non-suppurating lesions of nine patients with tropical myositis. When examined in an electron microscope, these revealed patchy myocytolysis with loss of band structure. Perimysial cells were also degenerate. Sections from two out of nine patients revealed intracellular vesicles, about 80 nm in diameter, some of which contained 10 nm granules. These vesicles were seen budding from cell membranes and resembled virus particles. The focal necrosis with which they are associated and their absence from control sections support the concept that they are related to the disease process.

Biventricular pacing in heart failure.

Optimal pharmacological therapy for heart failure improves patients' prognosis and symptoms. Despite this, the long-term prognosis for these patients is very poor and symptoms are debilitating. Biventricular pacing, or resynchronization therapy, should be considered for patients who remain symptomatic despite optimal therapy and have evidence of dyssynchrony.