Heritability of lumbar trabecular bone mechanical properties in baboons.

Genetic effects on mechanical properties have been demonstrated in rodents, but not confirmed in primates. Our aim was to quantify the proportion of variation in vertebral trabecular bone mechanical properties that is due to the effects of genes. L3 vertebrae were collected from 110 females and 46 male baboons (6-32 years old) from a single extended pedigree. Cranio-caudally oriented trabecular bone cores were scanned with microCT then tested in monotonic compression to determine apparent ultimate stress, modulus, and toughness. Age and sex effects and heritability (h(2)) were assessed using maximum likelihood-based variance components methods. Additive effects of genes on residual trait variance were significant for ultimate stress (h(2)=0.58), toughness (h(2)=0.64), and BV/TV (h(2)=0.55). When BV/TV was accounted for, the residual variance in ultimate stress accounted for by the additive effects of genes was no longer significant. Toughness, however, showed evidence of a non-BV/TV-related genetic effect. Overall, maximum stress and modulus show strong genetic effects that are nearly entirely due to bone volume. Toughness shows strong genetic effects related to bone volume and shows additional genetic effects (accounting for 10% of the total trait variance) that are independent of bone volume. These results support continued use of bone volume as a focal trait to identify genes related to skeletal fragility, but also show that other focal traits related to toughness and variation in the organic component of bone matrix will enhance our ability to find additional genes that are particularly relevant to fatigue-related fractures.

A locus on chromosome 13 influences levels of TAFI antigen in healthy Mexican Americans.

When activated, thrombin activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis by modifying fibrin, depressing its plasminogen binding potential. Polymorphisms in the TAFI structural gene (CPB2) have been associated with variation in TAFI levels, but the potential occurrence of influential quantitative trait loci (QTLs) located elsewhere in the genome has been explored only in families ascertained in part through probands affected by thrombosis. We report the results of the first genome-wide linkage screen for QTLs that influence TAFI phenotypes. Data are from 635 subjects from 21 randomly ascertained Mexican American families participating in the San Antonio Family Heart Study. Potential QTLs were localized through a genome-wide multipoint linkage scan using 417 highly informative autosomal short tandem repeat markers spaced at approximately 10-cM intervals. We observed a maximum multipoint LOD score of 3.09 on chromosome 13q, the region of the TAFI structural gene. A suggestive linkage signal (LOD = 2.04) also was observed in this region, but may be an artifact. In addition, weak evidence for linkage occurred on chromosomes 17p and 9q. Our results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may contribute strongly to TAFI level variation in the general population, although several genes in other regions of the genome may also influence variation in this phenotype. Our findings support those of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) project, which identified a potential TAFI QTL on chromosome 13q in a genome-wide linkage scan in Spanish thrombophilia families.

A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study.

OBJECTIVE: Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI. METHODS AND RESULTS: We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (P<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (P=0.04) was observed with the TFPI promoter variant C-399T. CONCLUSIONS: These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.

Myogenic adaptation of rabbit ear arteries to pulsatile internal pressures.

1. The effect of sinusoidal internal pressures on the constriction of in vitro, pressurized segments of ear arteries from rabbits has been examined. All arteries were constricted against a static transmural pressure of 60 mmHg to 35-60% of maximal, using extraluminal noradrenaline, before being exposed to the sinusoidal pressures. 2. There was a short period of adaptation when active arteries were first exposed to physiological pulsatile pressures. This adaptation had two components: a small, largely transient distension, lasting about 1 min, and sustained suppression of the distension produced by individual pressure pulses. 3. Constriction of adapted arteries was insensitive to physiological changes in pulse frequency (3-5 Hz), mean pulsatile pressure (60-120 mmHg), pulse amplitude (20-40 mmHg) and to alterations in pulse shape (sinusoidal, triangular and ramp). Over-all distension was restricted to 3.6 +/- 1.0% (S.D. of an observation) when the mean of a 3 Hz sinusoidal pressure of 30 mmHg amplitude was increased in steps from 75 to either 115 or 120 mmHg. 4. An initial distension was needed to initiate suppression of pressure pulse distension. Distension by individual pressure pulses, within a train of rectangular 60-90 mmHg pulses of 0.5 s duration, was maximally suppressed (85.6 +/- 1.3%; S.E. of mean, n = 9) at a pulse interval of 0.7 s. 5. Active ear arteries possess a myogenic mechanism capable of minimizing changes in constriction over the full physiological range of pulsatile internal pressures.

The interaction between noradrenaline activation and distension activation of the rabbit ear artery.

Excised, pressurized segments of the rabbit ear artery have been used to examine the interaction between the transmural pressure and constriction of arteries by extraluminal noradrenaline. The bath temperature was kept at 32-33 degrees C to suppress instability and spontaneity of constriction. Fast, reproducible jumps in pressure were obtained by using a microcomputer to control an electropneumatic transducer. The arteries did not react actively to transmural pressure changes unless already activated by noradrenaline. Active arteries responded to distension by a pressure jump with a reproducible compensatory constriction which was unaffected by tetrodotoxin. The counteraction of distension was due primarily to enhanced activation of the muscle. Distension activation decreased with increasing constriction. Utilization of the force-generating capacity of the arteries either remained unchanged at 20-30% or, in one experiment, increased slightly when constriction against a transmural pressure of 60 mmHg was increased from 20 to 75% of maximal by raising the noradrenaline concentration. When the transmural pressure was 90 mmHg, the 35-55% utilization of the force-generating capacity either remained constant or fell as constriction was increased. Most of the force-generating capacity was available for counteracting the distension of moderately constricted arteries (less than 40% of maximal) produced by a 60-90 mmHg jump. More than 78% of the maximum capacity was used in attempting to overcome the distension when it was maintained by computer-controlled increases in transmural pressure. The moderate constrictions were produced with noradrenaline concentrations which were 500-10,000 times lower than that used to maximally activate the arteries. The rabbit ear artery possesses a powerful, distension-sensitive mechanism that acts to minimize diameter changes initiated by transmural pressure jumps. The diameter of the active artery was determined by a combination of noradrenaline activation and distension activation for constrictions up to at least 75% of maximal. It is concluded that the interaction between noradrenaline activation and distension activation helps the muscle to fulfil the special functional requirements imposed by the geometry of tubes. This type of myogenic control system may be particularly well developed in those muscular blood vessels exposed to pulsatile internal pressures.

Ghanaian national policy toward indigenous healers. The case of the primary health training for indigenous healers (PRHETIH) program.

We review the policy of the Ghanaian Ministry of Health towards indigenous healers, and estimate their potential and actual utilization in the national health delivery system. We then describe the program to give primary health training to indigenous healers. The program established relations with the regional offices and central headquarters of the Ministry of Health. The Centre for Scientific Research into Plant Medicine, the Ghana Psychic and Traditional Healers Association and various categories of indigenous healers. We describe our strategies to coordinate the program with Ministry of Health Units and different categories of indigenous healers (mainly TBAs, herbalists and priest/priestess healers) in Techiman District. We analyze the socio-cultural, economic and politico-administrative forces impinging on the design and implementation of the program to recommend ways that this kind of program can be developed in other localities within and outside Ghana.

Traditional health workers: views from the field: moving well in both environments.

PIP: An integrated rural development program has been formed in Ghana, jointly sponsored by the Ministry of Health and WHO. Under the program, traditional birth attendants were given training and field experience. After examination, they were allowed to practice at the hospital and the village level, handling deliveries and referring high risk cases. Patient response has been favorable. Hospital staff have found the trained midwives to be useful.^ieng