Intrarenal angiotensin II is associated with inflammation,renal damage,and dysfunction in Dahl salt-sensitive hypertension

The goal of this study was to test the hypothesis that intrarenal angiotensin (Ang) II has a proinflammatory effect leading to renal damage and dysfunction in Dahl salt-sensitive (S) rats on high-Na intake. Forty-six 7- to 8-week old Dahl S or Dahl salt-resistant (R)/Rapp strain rats were maintained for 5 weeks on high sodium (8%) with or without candesartan cilexetil in daily doses of 10 to 15 mg/kg/day. Arterial catheters were implanted at day 28. By day 35 in the high-Na S + candesartan rats, renal tissue Ang II concentration, renal monocytes/macrophages, tumor necrosis factor-α, and monocyte chemoattractant protein-1 significantly decreased. Plasma Ang II remained at very low levels in all groups. Reduced renal damage in candesartan-treated Dahl S rats was demonstrated by marked decreases in urinary protein excretion and renal glomerular and interstitial damage. After 5 weeks of high-Na, compared with high-Na Dahl S rats, arterial pressure was unchanged in candesartan S rats, but creatinine clearance was increased. Therefore, candesartan reduced renal tissue Ang II, renal damage, infiltration of immune cells, cytokines, chemokines, and improved renal hemodynamics. These data suggest that intrarenal Ang II plays an important role in causing renal inflammation, which leads to renal cortical damage, proteinuria, and decreases in renal hemodynamics.     

‘Exercise snacks’ before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance

Aims/hypothesis

The aim of this study was to investigate whether small doses of intense exercise before each main meal (‘exercise snacks’) would result in better blood glucose control than a single bout of prolonged, continuous, moderate-intensity exercise in individuals with insulin resistance.

Methods

Nine individuals completed three exercise interventions in randomised order. Measures were recorded across 3 days with exercise performed on the middle day, as either: (1) traditional continuous exercise (CONT), comprising 30 min moderate-intensity (60% of maximal heart rate [HR_max]) incline walking before dinner; (2) exercise snacking (ES), consisting of 6?×?1 min intense (90% HR_max) incline walking intervals 30 min before each meal; or (3) composite exercise snacking (CES), encompassing 6?×?1 min intervals alternating between walking and resistance-based exercise, 30 min before meals. Meal timing and composition were controlled within participants for exercise interventions.

Results

ES attenuated mean 3 h postprandial glucose concentration following breakfast (by 1.4?±?1.5 mmol/l, p?=?0.02) but not lunch (0.4?±?1.0 mmol/l, p?=?0.22), and was more effective than CONT following dinner (0.7?±?1.5 mmol/l below CONT; p?=?0.04). ES also reduced 24 h mean glucose concentration by 0.7?±?0.6 mmol/l (p?=?0.01) and this reduction persisted for the subsequent 24 h (lower by 0.6?±?0.4 mmol/l vs CONT, relative to their baselines; p?=?0.01). CES was just as effective as ES (p?>?0.05 for all glycaemic variables) at improving glycaemic control.

Conclusions/interpretation

Dosing exercise as brief, intense ‘exercise snacks’ before main meals is a time-efficient and effective approach to improve glycaemic control in individuals with insulin resistance.     

Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic.

We have examined the role of cyclooxygenase 2 (COX-2) in a model of inflammation in vivo. Carrageenan administration to the subcutaneous rat air pouch induces a rapid inflammatory response characterized by high levels of prostaglandins (PGs) and leukotrienes in the fluid exudate. The time course of the induction of COX-2 mRNA and protein coincided with the production of PGs in the pouch tissue and cellular infiltrate. Carrageenan-induced COX-2 immunoreactivity was localized to macrophages obtained from the fluid exudate as well as to the inner surface layer of cells within the pouch lining. Dexamethasone inhibited both COX-2 expression and PG synthesis in the fluid exudate but failed to inhibit PG synthesis in the stomach. Furthermore, NS-398, a selective COX-2 inhibitor, and indomethacin, a nonselective COX-1/COX-2 inhibitor, blocked proinflammatory PG synthesis in the air pouch. In contrast, only indomethacin blocked gastric PG and, additionally, produced gastric lesions. These results suggest that inhibitors of COX-2 are potent antiinflammatory agents which do not produce the typical side effects (e.g., gastric ulcers) associated with the nonselective, COX-1-directed antiinflammatory drugs.     

Modulation of megakaryocytopoiesis by human basic fibroblast growth factor

Basic fibroblast growth factor (bFGF) may act to modulate hematopoiesis in addition to its effects on mesenchymal cells. We studied the effects of bFGF on human and murine primary marrow megakaryocytes. bFGF modestly enhanced the size of the human megakaryocyte colony-forming unit (CFU-MK) and cell numbers per colony, in combination with interleukin-3 (IL-3) or granulocyte-macrophage colony stimulating factor (GM-CSF). Adhesion of human megakaryocytes to bone marrow (BM) stromal fibroblasts was enhanced when either stromal fibroblasts or megakaryocytes were treated with bFGF. This resulted in significantly increased proliferation of megakaryocytes. In addition, bFGF augmented secretion of the cytokines tumor necrosis factor alpha and IL-6 by human primary BM megakaryocytes. Immature murine megakaryocytes showed a significant growth response to bFGF as measured by the single cell growth assay. This effect was abrogated by specific antibodies for bFGF and combination of anti-IL-6 and anti-IL-1 beta antibodies. bFGF has no effect on murine CFU-MK formation, but significantly potentiated CFU-MK formation in the presence of IL-3 or GM-CSF. These results indicate that the effect of bFGF on various megakaryocyte populations is different and that bFGF may affect megakaryocytopoiesis via modulation of megakaryocyte-stromal interactions and via augmentation of cytokine secretion from megakaryocytes.     

An innovative educational clinical experience promoting geriatric exercise

ABSTRACT

Formal educational training in physical activity promotion is relatively sparse throughout the medical education system. The authors describe an innovative clinical experience in physical activity directed at medical clinicians on a geriatrics rotation. The experience consists of a single 2 1/2 hour session, in which learners are partnered with geriatric patients engaged in a formal supervised exercise program. The learners are guided through an evidence-based exercise regimen tailored to functional status. This experience provides learners with an opportunity to interact with geriatric patients outside the hospital environment to counterbalance the typical geriatric rotation in which geriatric patients are often seen in clinics or hospitals. In this experience, learners are exposed to fit and engaged geriatric patients successfully living in the community despite chronic or disabling conditions. A survey of 105 learners highlighted positive responses to the experience, with 96% of survey respondents indicating that the experience increased their confidence in their ability to serve as advocates for physical activity for older adults, and 89.5% of responders to a follow-up survey indicating that the experience changed their perception of geriatric patients. Modifications to the experience, implemented at partnering facilities are described. The positive feedback from this experience warrants consideration for implementation in other settings.     

Radial access: So much progress but a way to go

• Transradial access is the key bleeding avoidance strategy in percutaneous coronary intervention.
• This study showed a marked adoption of transradial access over a 10‐year period, however, women had a significantly lower rate compared to men and overall bleeding events did not decrease over time.
• Strategies to overcome barriers to radial access in women and to maintaining competency in femoral access in all patients are needed.

     

Selective Aortic Arch Perfusion Using Serial Infusions of Perflubron Emulsion

Objective : To determine whether selective aortic arch perfusion (SAAP) using serial infusions of oxygenated perflubron emulsion combined with aortic epinephrine (AoE) administration is more effective than conventional therapy in treating cardiac arrest.
Methods : An experimental cardiac arrest model (10 min ventricular fibrillation and 2 min CPR) was used with 12 mixed-breed canines, randomized into 2 groups: control ( n = 6), CPR and IV epinephrine, 0.01 mgkg, at 12 rnin and then every 3 min; or AoE-SAAP ( n = 6), CPR and aortic epinephrine, 0.01 mgkg, at 12 rnin and then every 3 min, and serial SAAP with oxygenated 60% weightholume (w/v) perflubron emulsion as follows: 300 mL over 30 sec at 12 rnin as continuous SAAP without CPR; 150 mL over 20–30 sec at 15 min and 18 rnin as pulsed diastolic SAAP during CPR.
Results : AoE-SAAP resulted in increased coronary perfusion pressure (CPP) and return of spontaneous circulation (ROSC) compared with control. CPR-diastolic (release phase) CPP during pulsed diastolic SAAP was similar to or greater in magnitude than the CPP generated during the initial SAAP infusion without CPR. ROSC for control was 0/6 and for AoE-SAAP was 416 (p < 0.05, Fisher's exact test). Time from initiation of CPR to ROSC with a sustained systolic aortic pressure >60 mm Hg was 8.0 ± 1.2 rnin in the 4 resuscitated AoE-SAAP animals.
Conclusion : The combination of AoE with SAAP infusions of oxygenated perflubron emulsion was more effective than conventional resuscitation therapy. Pulsed diastolic SAAP is a promising method for performing SAAP.     

Itraconazole resistance in Aspergillus fumigatus.

Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.     

Cyclic thrombocytopenia of apparent autoimmune etiology

Serial studies were performed in two patients with cyclic thrombocytopenia to investigate the pathogenesis of this disorder. Mean life span of autologous platelets when platelet levels were declining was subnormal (2.4 and 0.8 days), and megakaryocytes were abundant in the bone marrow during thrombocytopenia. Megakaryocyte colony- stimulating activity could not be detected in the serum of either patient at any point of their cycles. In each patient, total platelet- associated IgG varied inversely with platelet levels. Surface platelet- associated IgG was measured only in patient 2 and was significantly elevated (greater than 1,280 IgG molecules per platelet) at all stages of the cycle, even during thrombocytosis. However, the highest values were observed during thrombocytopenia. Platelet-bindable IgG in plasma declined to normal immediately before platelet levels began to rise. IgG eluted from the platelets of this patient reacted strongly with autologous and homologous platelets in contrast to a "mock eluate" prepared from platelets of a normal subject. The eluate from the patient's platelets reacted strongly with immobilized autologous and homologous glycoprotein IIb/IIIa complex and weakly with GPIb but not with isolated GPIIIa alone. In each patient the decline in platelet levels was significantly delayed following administration of intravenous gamma globulin 0.4 g/kg body weight for five days. These findings suggest that platelet-reactive autoantibodies are of pathogenic significance in some patients with cyclic thrombocytopenia.