Superior cycle control with a contraceptive vaginal ring compared with an oral contraceptive containing 30 microg ethinylestradiol and 150 microg levonorgestrel: a randomized trial

BACKGROUND: This trial was conducted to compare cycle control with vaginal ring a combined contraceptive vaginal ring, and a combined oral contraceptive (COC) delivering 30 mug ethinylestradiol (EE) and 150 mug levonorgestrel. METHODS: This open-label, randomized, multi-centre, Phase III study involved adult women from 11 countries. Subjects were treated with either vaginal ring or a COC for 13 cycles (12 months). RESULTS: A total of 1030 subjects (vaginal ring, n=512; COC, n=518) comprised the intention-to-treat (ITT) population. The percentage of women in the ITT population who completed the trial was 70.9% for vaginal ring and 71.2% for the COC group. The incidence of breakthrough bleeding and spotting over cycles 2-13, the primary efficacy parameter, was lower with vaginal ring (range 2.0-6.4%) than the COC (range 3.5-12.6%), and for cycles 2 and 9 the lower incidence with vaginal ring was confirmed as statistically significant (P=0.003 and P=0.002 respectively). The incidence of intended bleeding was significantly higher over all cycles with vaginal ring (58.8-72.8%) than with the COC (43.4-57.9%). CONCLUSIONS: Cycle control with vaginal ring was excellent and superior to that of a COC containing 30 mug EE.     

Stunning and myocardial contractile autoregulation studied on the isolated isovolumic blood-perfused dog heart

AIM: To study, for the first time, the effects of stunning on homeometric and heterometric autoregulation. METHODS AND RESULTS: Ischaemia (15 min)/reperfusion (30 min) was induced in the isovolumic blood-perfused dog heart preparation. Heart rate elevations (n = 9) from 60 to 200 beats min-1, in steps of 20 beats min-1, promoted the same inotropic stimulation in control (C) and stunning (S), indicating that ischaemia/reperfusion does not affect the changes in calcium kinetics elicited by the Bowditch effect. Sudden ventricular dilation (VD) (n = 10) evoked an instantaneous increase in developed pressure (Delta1DP) followed by a continuous slow performance increase (Delta2DP) in C and S. Delta1DP (C: 35 +/- 2.2 mmHg; S: 27 +/- 2.1 mmHg; P = 0.002) and Delta2DP (C: 20 +/- 1.6 mmHg; S: 14 +/- 1.3 mmHg; P = 0.002) decreased proportionally, while Delta2/Delta1DP (C: 0.57 +/- 0.13; S: 0.58 +/- 0.14) and slow response time course (T/2) were unchanged (C: 55 +/- 6.6 s; S: 57 +/- 7.7 s) after ischaemia/reperfusion. The reduction of Delta1DP can be understood as a decline of the myofilaments calcium responsiveness, the main pathophysiological effect of stunning. The reason for the weakening of Delta2DP, due to intracellular calcium gain, was not determined but it was supposed that its complete manifestation could be restricted by cyclic adenosine monophosphate (cAMP) myocardial content reduction. As reported by others, Delta2DP depends on myocardial cAMP, and it has been shown that myocardial cAMP is decreased after ischaemia/reperfusion. CONCLUSIONS: Contractile depression due to stunning has no effect on the inotropic stimulation generated by the Bowditch phenomenon. Immediate and time-dependent enhancements of contraction evoked by sudden VD are proportionally reduced and the slow response time course is unaffected in the stunned myocardium.     

New studies on the Macushi Indians of northern Brazil

Demographic data and genetic information concerning 40 genetic systems are reported for three populations of Macushi Indians, and have been compared to those already obtained for three other communities of this tribe. These are young populations (mean age, 19 years), with a low sex ratio (90), low percentages of non-Indian ancestry (1-2%) and of marriages between locally born persons (34). Intertribal unions (14%) are less frequent than among their neighbours, the Wapishana. Fertility is high (average of 8.2 children per woman who completed reproduction), but the variance in family size and the frequency of premature deaths relatively low for populations at this cultural level. This conditions the lowest Index of Opportunity for Selection (0.45) calculated thus far among South American Indians. No variation was observed in 20 genetic systems, limited variation in 3, and larger variability in the remaining 17. In 13 of the 29 comparisons (45%), the Macushi gene frequencies present values in the middle third of the range observed among South American Indians. The previously reported private genetic polymorphism of esterase A was encountered in one of the three villages. A comparison of the genetic distances between villages with and without this polymorphism, and a similar comparison for the villages of the neighbouring Wapishana, yields no clue as to the tribe in which this polymorphism originated.     

Predisposing effect of spontaneous mesenchymal intimal thickenings of rabbit aorta to early lipid deposition

Summary Ten rabbits received by gastric tube 0.3 to 0.8 g pure cholesterol every second day for 4 to 8 weeks. Ten animals were used as control. Total serum cholesterol was determined weekly in experimental and control groups. The mean value of the total serum cholesterol in the experimental group was 482±79.6 mg/100 ml, about 2.5 times more than the cholesterol value of the control group (206±51.0 mg/100 ml).Early and selective lipid deposition was present in spontaneous mesenchymal thickenings of all aortas of the animals receiving cholesterol. The deposition failed to be observed in the aortic intima without that thickening. The intimal thickening is a change of the arterial wall that predisposes to lipid deposition.This observation supports the view that the proliferative changes seen in human atherosclerosis precede the lipid deposition and are a predisposing factor to this deposition.     

The CARD15 2936insC mutation and TLR4 896 A>G polymorphism in African Americans and risk of preterm premature rupture of membranes (PPROM)

Infection is believed to be a leading cause of preterm premature rupture of membranes (PPROM). The bacterial cell wall component, lipopolysaccharide (LPS), is thought to initiate tissue responses leading to PPROM in the setting of Gram negative infection. LPS is recognized by the innate immune system, including the proteins encoded by the CARD15 and TLR4 genes. A recently described mutation (2936insC) in CARD15 and a polymorphism in TLR4 896 A>G impair responses to LPS. The objective of this study was to determine if African Americans, who have a higher incidence of PPROM than Caucasians, have different frequencies of the mutant CARD15 allele and the TLR4 hyporesponsive variant, and if risk of PPROM is influenced by fetal carriage of these alleles. The allele frequencies for the CARD15 mutation and the TLR4 896G variant in African Americans were similar to those reported for Caucasians. There was no association between the TLR4 alleles examined and PPROM. However, the CARD15 mutation was only detected in controls and not in PPROM cases. We conclude that the CARD15 mutation and hyporesponsive TLR4 allele do not contribute to ethnic variation in the incidence of PPROM.     

Inhibition of cysteine proteinases by autolytic digestion is mediated by CBP2/Hsp47

CBP2/Hsp47 is a glycoprotein normally limited to the ER-Golgi where it is first associated with procollagen chains at a very early point during translation of nascent chains and later with properly folded procollagen. Although CBP2/Hsp47 is regarded as a molecular chaperone belonging to the serpin superfamily, this protein does not appear to inhibit serine proteinases. Here we demonstrate that CBP2/Hsp47 functions in a manner similar to other serpin superfamily members by cross class inhibiting cysteine proteinases. A CBP2/Hsp47 to cathepsin L inactivation stoichiometery of approximately 1.5 revealed concurrent cleavage of CBP2/Hsp47 with proteinase inactivation. Cleavage of the CBP2/Hsp47 was shown to occur outside the P1-P1' at the P16-P15 and P2'-P3' bonds. In addition, the proteinase bands in SDS/PAGE diminished on reaction of the enzyme with CBP2/Hsp47. These results sustain a mechanism advocated by Bjork et al. (1998), in which cysteine proteinases assault a peptide bond in the reactive site loop of serpins, (CBP2/Hsp47) adjacent to the P1-P1' bonds involved in serine proteinase inhibition. The reaction proceeds with the substrate pathway dominating in the cysteine proteinase reaction. In these complexes the cysteine proteinases, papain and cathepsin L, are rendered more susceptible to proteolysis and are degraded by active enzyme. These properties help explain the mechanism by which CBP2/Hsp47 increases the fidelity of collagen production. Moreover, if CBP2/Hsp47 is shown to involve the multiplexin subclass of collagens, it may further provide a mechanism by which the motogen and angiogenic properties during development and/or neoplasia are regulated.     

Inverse association between skin response to aeroallergens and Schistosoma mansoni infection

BACKGROUND: Helminthic infections and allergic disease are highly prevalent in many areas of the world. It is known that IgE antibodies are involved in the pathogenesis of both helminthiasis and atopy. However, the consequences of the presence of helminthic infections in atopic patients are still not completely understood. METHODS: Subjects infected by Schistosoma mansoni with more than 200 eggs/g of feces (n = 42) and uninfected subjects (n = 133) were selected from an endemic area of schistosomiasis. The history of allergy and results of the immediate hypersensitivity prick tests with inhalant allergen extracts were registered. Total IgE and IgE specific to S. mansoni and aeroallergens were measured in serum by ELISA. RESULTS: The proportion of individuals with a positive skin test to allergens was higher in the uninfected group (24.3%) than in the group with more than 200 eggs/g of feces (4.8%). The odds of atopy (defined as a positive test for at least one of the antigens) were 5 times higher (odds ratio = 7.0; 95% confidence interval = 1.6-31.1%; p = 0.01) in the uninfected group, after taking into account the potential influence of gender and age. While there was a tendency for higher total and S. mansoni-specific IgE levels in infected patients, an opposite trend, that is higher aeroallergen-specific IgE, was observed in uninfected subjects. CONCLUSIONS: There was a strong and statistically significant inverse association between the immediate skin test response to common aeroallergens and infection by S. mansoni. The results indicate that immediate hypersensitivity reactions may be suppressed in S. mansoni-infected individuals.     

Induction of a cytotoxic T cell response by co-injection of a T helper peptide and a cytotoxic T lymphocyte peptide in incomplete Freund's adjuvant (IFA): Further enhancement by pre-injection of IFA alone

We have previously demonstrated that it is possible to induce a consistent and strong cytolytic T lymphocyte (CTL) response to synthetic peptides, corresponding to poorly immunogenic malaria CTL epitopes, by co-injecting them with peptides representing defined T helper (Th) epitopes in incomplete Freund's adjuvant (IFA). In this study we have tested different immunization protocols to improve further the elicitation of the CTL response. We show that the CTL response to a mixture of Th + CTL peptides administered in IFA was further enhanced by a previous injection of the Th epitope peptide in IFA. Moreover, we found that the response could be significantly augmented by a pre-injection of IFA alone. This enhancement was observed only if the Th epitope was also present in the second injection. The number of lymph node cells recovered was 2–3-fold higher in mice pre-injected with IFA, but the increase in specific CTL activity, expressed as lytic units per animal, by pre-injection of IFA was at least 10–20-fold. Thus, pre-injection of IFA clearly increases the magnitude of a subsequent CTL response.