Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study

The Scandinavian Simvastatin Survival Study (4S) was a double-blind. randomized placebo-controlled multi-centre clinical trial of long-term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/1, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.     

Regulation of human natural killer (NK) cell function: Induction of killing of an NK-resistant renal carcinoma cell line

Natural killer (NK)-like activity against a renal carcinoma cell line, Cur, was assessed. There was no spontaneous killing of Cur cells by human peripheral blood mononuclear cells in 4-hr assays. Cur killing was observed in 18-hr assays, but the magnitude of killing was variable and always markedly less than that against K562. Cur killing was mediated by a nonadherent, nonphagocytic lymphocyte, the activity of which could be modulated both positively and negatively by monocytes or their products. Preincubation of effectors with monocyte supernatant, interleukin 1 (IL-1), -interferon (IFN), or interleukin 2 (IL-2) greatly increased the magnitude of Cur killing and accelerated the kinetics of lysis. The addition of prostaglandin E₂ (PGE₂) duringin vitro activation of NK by IL-2 profoundly inhibited subsequent Cur lysis, whereas only minimal inhibition of K562 lysis was noted. However, following activation with IL-2, lysis of Cur targets was less sensitive to the inhibitory effects of PGE₂. Removal of Leu 11b(+), OKM1(+), orl-leucylleucine methyl ester-sensitive cells markedly decreased both Cur and K562 lysis. Moreover, CD16(+) cells purified with the fluorescence-activated cell sorter were found to mediate Cur killing. Whereas Cur and K562 lysis is mediated by phenotypically similar effector cells, the present studies demonstrate that the cytotoxic functions defined by the ability to lyse these two targets differ in response to a variety of immunoregulatory stimuli.     

Hyperthermia and maximal oxygen uptake in men and women

To compare the effect of hyperthermia on maximal oxygen uptake (O_2max) in men and women, O_2max was measured in 11 male and 11 female runners under seven conditions involving various ambient temperatures (T_a at 50% RH) and preheating designed to manipulate the esophageal (T_es) and mean skin temperatures at O_2max. The conditions were: 25°C, no preheating (control); 25, 35, 40, and 45°C, with exercise-induced preheating by a 20-min walk at ~33% of control O_2max; 45°C, no preheating; and 45°C, with passive preheating during which T_es and were increased to the same degree as at the end of the 20-min walk at 45°C. Compared to O_2max (l·min^–1) in the control condition (4.52±0.46 in men, 3.01±0.45 in women), O_2max in men and women was reduced with exercise-induced or passive preheating and increased T_a, ~4% at 35°C, ~9% at 40°C and ~18% at 45°C. Percentage reductions (7–36%) in physical performance (treadmill test time to exhaustion) were strongly related to reductions in O_2max (r=0.82–0.84). The effects of hyperthermia on O_2max and physical performance in men and women were almost identical. We conclude that men and women do not differ in their thermal responses to maximal exercise, or in the relationship of hyperthermia to reductions in O_2max and physical performance at high temperature. Data are reported as mean (SD) unless otherwise stated.     

Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease

The present study, using robotized DNA isolation and quantitative PCR based on the Neisseria meningitidis-specific capsular transport A gene, demonstrates the ease, rapidity, specificity, and sensitivity of quantifying neisserial DNA in plasma (n = 65) and cerebrospinal fluid (CSF) (n = 12) from patients with systemic meningococcal disease. We found a close correlation between the levels of neisserial DNA and lipopolysaccharides in plasma (r = 0.905) and in CSF (r = 0.964). The median concentration of neisserial DNA in plasma in 23 patients with persistent shock was 2 x 10(7) copies/ml, versus <10(3) copies/ml in 42 nonshock patients. Furthermore, quantitative PCR made possible estimates of the total number of meningococci in plasma, as opposed to conventional blood cultures, suggesting about 1,000 dead meningococci for every viable bacterium. Finally, with logistic regression analyses, neisserial DNA may predict a patient's disease severity and outcome at hospital admission. The number of meningococci in plasma and CSF appears to be the main determinant of the lipopolysaccharide levels, clinical presentation, and outcome.     

DNA content and expression of tumour markers in germ cells adjacent to germ cell tumours in childhood: Probably A different origin for infantile and adolescent germ cell tumours

The origin of testicular germ cell tumours occurring during childhood is poorly understood. In adults, the classical seminomas and non-seminomas originate from carcinoma in situ of the testis, which can usually also be detected in seminiferous tubules adjacent to the tumours. In order to contribute with information regarding a possible association between carcinoma in situ and the childhood group of germ cell tumours, we investigated seminiferous tubules adjacent to 13 infantile yolk sac tumours, five infantile teratomas, and six adolescent germ cell tumours of various types, using morphological evaluation, immunohistochemical staining with markers for carcinoma in situ cells, and densitometric DNA measurement of the germ cells. We detected clear differences between the germ cell populations adjacent to adolescent and infantile germ cell tumours. The former were associated with both normal germ cells and carcinoma in situ cells. The presence of carcinoma in situ cells strongly suggested that the adolescent tumours arose from carcinoma in situ cells, like germ cell tumours occurring in adult men. Although we were in doubt in two cases, the infantile germ cell tumours were in general not associated with carcinoma in situ cells. The aetiology of infantile yolk sac tumours and teratomas may therefore be fundamentally different from that of adolescent and adult germ cell tumours. The origin of yolk sac tumours and teratomas remains to be elucidated.     

Messenger RNA processing sites in Trypanosoma brucei

In Kinetoplastids, protein-coding genes are transcribed polycistronically by RNA polymerase II. Individual mature mRNAs are generated from polycistronic precursors by 5' trans splicing of a 39-nt capped leader RNA and 3' polyadenylation. It was previously known that trans splicing generally occurs at an AG dinucleotide downstream of a polypyrimidine tract, and that polyadenylation is coupled to downstream trans splicing. The few polyadenylation sites that had been examined were 100-400 nt upstream of the polypyrimidine tract which marked the adjacent trans splice site. We wished to define the sequence requirements for trypanosome mRNA processing more tightly and to generate a predictive algorithm. By scanning all available Trypanosoma brucei cDNAs for splicing and polyadenylation sites, we found that trans splicing generally occurs at the first AG following a polypyrimidine tract of 8-25 nt, giving rise to 5'-UTRs of a median length of 68 nt. We also found that in general, polyadenylation occurs at a position with one or more A residues located between 80 and 140 nt from the downstream polypyrimidine tract. These data were used to calibrate free parameters in a grammar model with distance constraints, enabling prediction of polyadenylation and trans splice sites for most protein-coding genes in the trypanosome genome. The data from the genome analysis and the program are available from: .     

Changes in the surface electromyogram during increasing isometric shoulder forward flexions

Summary When using electromyographic techniques in the evaluation of muscular load it is necessary to determine the mathematical relationship between the torque and the amplitude of the electromyographic signal. Isometric gradually increasing contractions up to 100% MVC can then be used. Often more than linear increases for the amplitude (RMS) — force regression have been reported. The present study was designed to test whether changes in power spectral density function take place during a gradually increasing isometric contraction (duration 10 s). Twenty-two clinically healthy females performed an increasing isometric shoulder forward flexion for 10 s using an isokinetic dynamometer. Electromyographic activity was measured in trapezius, deltoid, infraspinatus and biceps brachii using surface electrodes. Mean torque values were determined together with mean power frequency (MPF) and root mean square values (RMS) from the EMG signals for each 256 ms period. The RMS-torque regressions showed higher regression coefficients during the 6th to 9th sec than during the first 5 s. No significant correlation existed between MPF for the four muscles and the torque. A gradual decrease in MPF was generally found from the 6th s. It is concluded that this decrease in power spectral density function might have contributed to the significantly higher regression coefficient for the RMS torque regression at the high output part of the gradually increasing isometric contraction.     

Muscular fatigue during repeated isokinetic shoulder forward flexions in young females

Summary Peak torque, work, mean power and electromyographic (EMG) activity were recorded for each of 150 repeated isokinetic maximal shoulder flexions (45°–90°) in 23 healthy females. From the EMG signals of trapezius, deltoid, infraspinatus and biceps brachii the mean power frequency and the signal amplitude were determined in real time. The mechanical output showed a steep decrease during the first 40 contractions, followed by a plateau maintained until the end. In all muscles, except the biceps brachii, significant decreases in mean power frequency occurred during the first 40 contractions, showing a tendency to stabilize around the same absolute frequency value. Signal amplitude increased in the trapezius, the deltoid and the infraspinatus, but was constant in the biceps brachii. For some individuals rather high EMG activity was recorded in the muscles during the time the arm was supposed to be passively extended to the starting position, and this was found to be associated with lower strength and endurance levels. Longitudinal analyses showed that the mean power frequencies correlated better than the signal amplitudes with the three mechanical variables. The results suggest that the initial steep decrease in mechanical performance and mean power frequency is caused by fatiguing of type 2 motor units.     

Tetrodotoxin block of A-fibre afferents from skin and muscle - a tool to study pure C-fibre effects in the spinal cord

The properties of tetrodotoxin (TTX)-resistant C-fibre afferents of the dorsal roots were tested in Sprague-Dawley rats. Dorsal roots (L4-L6) were blocked with TTX (0.5-1 micro M) and the amplitude of the first response of the dorsal horn superficial interneurones (cord dorsum potential, CDP) to electrical stimulation of peripheral C-fibres in combination with natural noxious stimulation was taken as measure for intact conductivity of different kinds of noxious input by means of the C-fibre refractory period. After blockade of dorsal roots with TTX, formerly masked CDPs from muscle C-fibre afferents were uncovered. Noxious pressure to the gastrocnemius soleus muscle belly and noxious pinch to the calcanean tendon proved to be TTX resistant and therefore was propagated centrally. For cutaneous heat nociceptors it could also be shown that conductivity was intact after blockade of the dorsal roots with TTX. However, we could not exclude the TTX resistance of non-nociceptive receptors of muscle or skin. Nevertheless, blockade of afferents with TTX together with suitable stimulation techniques proves to be a reliable method to investigate central effects from C-fibre afferents without contaminating effects from A-fibres in the rat.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society