Myocardial lactate release during prolonged exercise under hypoxaemia

The possible appearance of myocardial lactate production during exercise under hypoxaemia, simulating an altitude of about 4500 metres above sea-level (masl) was investigated. Twelve healthy men were studied, after coronary sinus catheterization, during prolonged exercise breathing 12% 0₂ compared with men breathing air. Coronary sinus blood flow was measured by thermodilution. Exercise duration under each breathing condition was 30 min and the order normoxaemia/hypoxaemia was varied between subjects so as to compensate for any influence of a preceding exercise period on a subsequent one. Work load was adjusted so as to produce a heart rate (HR) of 130–140 beats min^-1 during both hypoxaemia and normoxaemia. [¹⁴C]lactate was infused at a constant rate i.v. throughout the study to detect a possible myocardial lactate release simultaneously with a net uptake. Myocardial 0₂ uptake did not differ significantly between hypoxaemia and normoxaemia. The compensation for reduced blood oxygen content was achieved entirely by a greater coronary blood flow. Yet, the arterial-coronary sinus (a-cs) lactate difference was lower during hypoxaemia than normoxaemia and isotope data indicated that this was caused by a myocardial lactate release of approximately 90 μmol min^-1 which was at hand during hypoxaemia but not normoxaemia, whether hypoxaemic exercise preceded or succeeded normoxaemic exercise. In conclusion, A 27% reduction in arterial oxygen saturation is almost compensated for by an increased coronary blood flow. However, during hypoxaemic exercise cardiac energy demand is to a smaller part, about 1 %, covered by anaerobic metabolism.     

Relative antithrombotic effects of monoclonal antibodies targeting different platelet glycoprotein-adhesive molecule interactions in nonhuman primates

The relative antithrombotic effectiveness of targeting glycoprotein (GP) Ib-dependent versus GPIIb-IIIa-dependent platelet interactions has been determined in baboons by measuring thrombus formation after infusing comparable antihemostatic doses of anti-von Willebrand factor (vWF) monoclonal antibody (MoAb) BB3-BD5, anti-GPIb MoAb AP1, and anti- GPIIb-IIIa MoAb LJ-CP8 under conditions of arterial and venous flow (shear rates of 750 to 1,000 seconds-1 and 100 seconds-1, respectively). Thrombus formation was quantified as 111In-platelet deposition and 125I-fibrin accumulation on segments of collagen-coated tubing interposed in chronic exteriorized arteriovenous (AV) shunts for 40 minutes. In vitro, anti-vWF MoAb BB3 BD5 (IgG) and anti-GPIb MoAb AP1 [IgG or F(ab)2 fragments] inhibited ristocetin-induced platelet aggregation (IC50 50 nmol/L and 1 mumol/L, respectively), but neither of these MoAbs blocked platelet aggregation induced by adenosine diphosphate (ADP) (P > .5). Conversely, anti-GPIIb-IIIa MoAb LJ-CP8 inhibited platelet aggregation induced by ADP (IC50 1 mumol/L, but failed to block ristocetin-induced platelet aggregation (P > .5). In vivo, the intravenous infusion of anti-vWF MoAb BB3 BD5 or anti-GPIIb- IIIa MoAb LJ-CP8 into baboons at doses that abolished corresponding agonist-induced aggregation ex vivo (bolus injections of 0.5 mg/kg and 10 mg/kg, respectively) prolonged template bleeding times from baseline values of 4.0 +/- 0.3 minutes to > 27 +/- 4 minutes, and to > 26 +/- 4 minutes, respectively (P < .001 in both cases), without affecting the peripheral platelet count (P > .5). However, injection of anti-GPIb MoAb AP1 [10 mg/kg as IgG or 1 mg/kg as F(ab)2 fragments] produced immediate irreversible thrombocytopenia (< 40,000 platelets/microL). Anti-GPIIb-IIIa MoAb LJ-CP8 abolished platelet deposition and fibrin accumulation on collagen segments under both arterial and venous flow conditions (P < .01 in all cases), whereas MoAb BB3 BD5 produced minimal inhibition of platelet deposition and no decrease in fibrin accumulation at arterial shear rates and undetectable antithrombotic outcomes at low shear. Thus, inhibiting GPIIb-IIIa-dependent platelet recruitment abrogates both thrombus formation and platelet hemostatic function at both venous and arterial shear rates. By contrast, interfering with GPIb-vWF-dependent platelet interactions abolishes platelet hemostatic function without producing corresponding antithrombotic effects.     

Fever and neutropenia: bacterial etiology revealed by serological methods

In a prospective study, 91 episodes of fever in neutropenic children with cancer were evaluated. Fifteen episodes were septicemias, verified by a positive blood culture, 62 were fevers of unknown origin, 6 were focal infections and 8 were of other etiologies (i.e. drug fevers and viral infections). Serum antibody responses to bacteria were measured in paired sera by an enzyme immunoassay method. Bacterial infection was demonstrated serologically in 20% of documented septicemias, in 35% of fevers of unknown origin and occasionally in the other groups. Tests were available and found positive in the fever of unknown origin group for Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and enterobacteria. Some had multiple etiology. In conclusion, bacterial serology is a promising method of identifying bacterial etiology in fever of otherwise unknown origin in neutropenic children with cancer.     

The evolving story of the RAAS in hypertension, diabetes and CV disease – moving from macrovascular to microvascular targets

The phylogenetically old renin-angiotensin-system (RAS) was originally described as a circulating hormonal system and a main cardiovascular regulator. However, there also exist 'local RASs' which are situated in cardiovascular as well as non-cardiovascular tissues where they are involved in physiological and patho-physiological processes such as inflammation, fibrosis, proliferation or apoptosis. Local RASs are activated in diabetes, preferentially in organs affected by hyperglycaemic injury such as the kidney or the retina. Increased renal or retinal Ang II levels may contribute to diabetic tissue injury in two ways: (i) by stimulating the angiotensin AT1-receptor and downstream pathological chains of events and (ii) by bidirectional interaction with the 'classical' hyperglycaemia-induced pathobiochemical pathways (oxidative stress, generation of advanced glycation end products, increased polyol pathway flux, activation of protein kinase C, increased hexosamine pathway flux). The involvement of the RAS in the pathomechanisms underlying diabetic end organ damage suggests pharmacological RAS inhibition as a therapeutic approach in these disorders. This assumption has been supported by numerous animal studies. Clinically, RAS inhibition is currently the first line, guideline-approved treatment in diabetic nephropathy. The recently published DIRECT, RASS and AdRem studies provided evidence that RAS inhibition may also be beneficial in diabetic retinopathy; however, evidence for RAS-inhibition in retinopathy is still much weaker than for nephropathy. The present article reviews the emerging knowledge about cardiovascular and non-cardiovascular effects of the RAS with an emphasis on the mechanisms of RAS involvement and pharmacological RAS inhibition in diabetic end organ damage.     

HYDRA: possible determinants of unsatisfactory hypertension control in German primary care patients

The Hypertension and Diabetes Screening and Awareness (HYDRA) study is a cross-sectional point-prevalence study performed in September 2001; 45,125 primary care attendees were recruited from a representative nationwide sample of 1912 primary care practices in Germany. Around 42% of all patients presenting in these practices had hypertension (WHO definition). In approximately 70% of these patients, hypertension was diagnosed by doctors and 84% of diagnosed patients were on antihypertensive medication, but in less than 30% of treated patients was blood pressure controlled (< 140/90 mmHg). The control rate in all patients presenting with hypertension (including those patients unrecognized) was as low as 19%. The present analysis aimed to find explanations for this unsatisfactory outcome of hypertension control. The main finding was that the rate of diagnosis of hypertension is alarmingly low in young people, probably due to insufficient blood pressure screenings. The data further indicated that doctors still set their target of treatment according to outdated guidelines and that doctors still orientate their treatment primarily with regard to the diastolic pressure. These insights into the causes of unsatisfactory hypertension control may help to direct future educational programmes designed to improve hypertension management specifically to these deficits and thereby to improve control rates.