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Biomedical subjects

R Mo

Publications and source records attributed to R Mo.

At least 19 recordsLinked to original sources
PubMed1998

Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study.

We tested the hypothesis that genetic variation in the beta-2 adrenoceptor gene is associated with a genetic predisposition to hypertension. Offspring of two hypertensive parents were compared with offspring of two normotensive parents. The subjects were participants of the Bergen Blood Pressure Study, where couples were recruited in 1963 to 1964 and re-examined in 1990. We studied offspring of those couples in which both partners were either hypertensive or normotensive in both examinations. Twenty-three hypertensive and 22 normotensive families met the inclusion criteria. DNA samples from the first born of hypertensive family-history offspring and normotensive family-history offspring were analyzed. We used multiplex sequencing and specifically examined the promoter and the N-terminal portion of the beta-2 adrenoceptor gene. We found four genetic variants: at position -47, a C-->T substitution in the 5' leader cistron causing an Arg-->Cys exchange, at -20, a T-->C substitution, at +46 an A-->G substitution leading to an Arg16-->Gly exchange, and at +79, a C-->G substitution leading to a Gln27-->Glu exchange. The frequency of the Arg16 allele was significantly higher in the hypertensive family-history offspring compared to normotensive family-history offspring (58% vs. 28% P < 0.011). We constructed haplotypes for the four intragenic variants and found significant linkage dysequilibrium. In particular, the 5' leader cistron mutant with the wild type alleles at the other loci was significantly more frequent in offspring of hypertensive parents, compared to offspring of normotensive parents. We also performed a relative risk analysis comparing the Gly/Gly, Arg/Gly, and Arg/Arg alleles, which implicated the Arg-containing allele. Finally, we analyzed the effect of genotype on blood pressure in the offspring. We found a significant step-wise effect for all four polymorphisms examined. Our data suggest that the Arg variant of the Arg-->Gly exchange is associated with parental hypertension and higher blood pressure values in this northern European population.

Adult↗
PubMed1998

Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice.

Floor plate cells at the midline of the neural tube are specified by high-level activity of Sonic hedgehog (Shh) secreted by notochord, whereas motor neurons are thought to be specified by a lower level activity of Shh secreted in turn by floor plate cells. In Drosophila, the Gli zinc finger protein Cubitus interruptus functions as a transcription factor activating Hedgehog-responsive genes. We report that the expression of known Shh-responsive genes such as Ptc and Gli1 is downregulated in mutant mice lacking Gli2 function. Gli2 mutants fail to develop a floor plate yet still develop motor neurons, which occupy the ventral midline of the neural tube. Our results imply that Gli2 is required to mediate high level but not low level Shh activity and show that the development of motor neurons can occur in the absence of floor plate induction.

Animals↗
PubMed1998

The Shh signalling pathway in tooth development: defects in Gli2 and Gli3 mutants.

The expression of genes involved in the Sonic Hedgehog signalling pathway, including Shh, Ptc, Smo, Gli1, Gli2 and Gli3, were found to be expressed in temporal and spatial patterns during early murine tooth development, suggestive of a role in early tooth germ initiation and subsequent epithelial-mesenchymal interactions. Of these Ptc, Smo, Gli1, Gli2 and Gli3 were expressed in epithelium and mesenchyme whereas Shh was only detected in epithelium. This suggests that Shh is involved in both lateral (epithelial-mesenchymal) and planar (epithelial-epithelial) signalling in early tooth development. Ectopic application of Shh protein to mandibular mesenchyme induced the expression of Ptc and Gli1. Addition of exogenous Shh protein directly into early tooth germs and adjacent to tooth germs, resulted in abnormal epithelial invagination, indicative of a role for Shh in epithelial cell proliferation. In order to assess the possible role of this pathway, tooth development in Gli2 and Gli3 mutant embryos was investigated. Gli2 mutants were found to have abnormal development of maxillary incisors, probably resulting from a mild holoprosencephaly, whereas Gli3 mutants had no major tooth abnormalities. Gli2/Gli3 double homozygous mutants did not develop any normal teeth and did not survive beyond embryonic day 14.5; however, Gli2(-/-); Gli3(+/-) did survive until birth and had small molars and mandibular incisors whereas maxillary incisor development was arrested as a rudimentary epithelial thickening. These results show an essential role for Shh signalling in tooth development that involves functional redundancy of downstream Gli genes.

Animals↗
PubMed1997

Activation of stress-activated protein kinases/c-Jun N-terminal protein kinases (SAPKs/JNKs) by a novel mitogen-activated protein kinase kinase.

Mitogen-activated protein kinase (MAPK) kinases (MKKs) are dual-specificity protein kinases that phosphorylate and activate MAPK. We have isolated a cDNA encoding a novel protein kinase that has significant homology to MKKs. The novel kinase MKK7 has a nucleotide sequence that encodes an open reading frame of 347 amino acids with 11 kinase subdomains. MKK7 is ubiquitously expressed in all adult and embryonic organs but displays high expression in epithelial tissues at later stages of fetal development. When transiently expressed in 293 cells, MKK7 specifically activated stress-activated protein kinases (SAPKs)/c-Jun N-terminal protein kinases (JNKs) but not extracellular-regulated kinase or p38 kinase. A kinase-negative mutant of MKK7 inhibits interleukin-1beta, lipopolysaccharide, and MEKK1-induced SAPK/JNK activation. Thus, MKK7 is a new member of the MAPK kinase family that functions upstream of SAPK/JNK in the SAPK/JNK signaling pathway.

Amino Acid Sequence↗
PubMed1997

Brca2 is required for embryonic cellular proliferation in the mouse.

Mutations of the tumor suppressor gene BRCA2 are associated with predisposition to breast and other cancers. Homozygous mutant mice in which exons 10 and 11 of the Brca2 gene were deleted by gene targeting (Brca2(10-11)) die before day 9.5 of embryogenesis. Mutant phenotypes range from severely developmentally retarded embryos that do not gastrulate to embryos with reduced size that make mesoderm and survive until 8.5 days of development. Although apoptosis is normal, cellular proliferation is impaired in Brca2(10-11) mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 is increased. Thus, Brca2(10-11) mutants are similar in phenotype to Brca1(5-6) mutants but less severely affected. Expression of either of these two genes was unaffected in mutant embryos of the other. This study shows that Brca2, like Brca1, is required for cellular proliferation during embryogenesis. The similarity in phenotype between Brca1 and Brca2 mutants suggests that these genes may have cooperative roles or convergent functions during embryogenesis.

Animals↗
PubMed1997

Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development.

The correct patterning of vertebrate skeletal elements is controlled by inductive interactions. Two vertebrate hedgehog proteins, Sonic hedgehog and Indian hedgehog, have been implicated in skeletal development. During somite differentiation and limb development, Sonic hedgehog functions as an inductive signal from the notochord, floor plate and zone of polarizing activity. Later in skeletogenesis, Indian hedgehog functions as a regulator of chondrogenesis during endochondral ossification. The vertebrate Gli zinc finger proteins are putative transcription factors that respond to Hedgehog signaling. In Drosophila, the Gli homolog cubitus interruptus is required for the activation of hedgehog targets and also functions as a repressor of hedgehog expression. We show here that Gli2 mutant mice exhibit severe skeletal abnormalities including cleft palate, tooth defects, absence of vertebral body and intervertebral discs, and shortened limbs and sternum. Interestingly, Gli2 and Gli3 (C.-c. Hui and A. L. Joyner (1993). Nature Genet. 3, 241-246) mutant mice exhibit different subsets of skeletal defects indicating that they implement specific functions in the development of the neural crest, somite and lateral plate mesoderm derivatives. Although Gli2 and Gli3 are not functionally equivalent, double mutant analysis indicates that, in addition to their specific roles, they also serve redundant functions during skeletal development. The role of Gli2 and Gli3 in Hedgehog signaling during skeletal development is discussed.

Animals↗
PubMed1996

The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.

Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/- mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca1(5-6) mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers.

Alternative Splicing↗
PubMed1996

Fourth component of Xenopus laevis complement: cDNA cloning and linkage analysis of the frog MHC.

Complement C4 shows extensive structural and functional similarity to complement C3, hence these components are believed to have originated by gene duplication from a common ancestor. Although to date C3 cDNA clones have been isolated from all major classes of extant vertebrates including Xenopus, C4 cDNA clones have been isolated from mammalian species only. We describe here the molecular cloning and structural analysis of Xenopus C4 cDNA. The cDNA sequence encoding the thioester region of Xenopus C4 was amplified by reverse transcriptase-polymerase chain reaction using Xenopus liver mRNA as a template, and then used to screen a liver cDNA library. The amino acid sequence of Xenopus C4 deduced from a clone containing the entire protein-coding sequence showed 39%, 30%, 25%, and 20% overall identity with those of human C4, C3, C5, and alpha2-macroglobulin, respectively. The predicted amino acid sequence consisted of a 22-residue putative signal peptide, a 634-residue beta chain, a 732-residue alpha chain, and a 287-residue gamma chain. Of 30 cysteine residues, 27 were found in exactly the same positions as in human C4. Genomic Southern blotting analysis indicated that C4 is a single copy gene in Xenopus and is part of the frog MHC cluster. These results clearly demonstrate that C3/C4 gene duplication and linkage between the C4 gene and the major histocompatibility complex predate mammalian/amphibian divergence.

Amino Acid Sequence↗
PubMed1995

The Bergen Blood Pressure Study: prehypertensive changes in cardiac structure and function in offspring of hypertensive families.

Cardiac morphology and function were determined by echocardiography in normotensive offspring of 23 hypertensive and 22 normotensive families. The family histories of hypertension or normotension were based on 27 years' observation of parental blood pressure. Pulsed Doppler and M-mode echocardiography were performed in standard views. Out of the total 109 offspring, 94 participated in the present study (age (mean +/- SD) 36 +/- 7 years). Left ventricular posterior wall thickness was higher in offspring of hypertensive than normotensive families (10.1 +/- 1.7 vs. 9.3 +/- 1.5 mm; p < 0.05). Offspring of hypertensive families had lower transmitral early/late peak flow velocities (p < 0.001) and higher transmitral late peak flow velocities (p < 0.001) than offspring of normotensive families, but the differences between groups became inconsistent after adjustment for confounding variables (including left ventricular structural parameters). On the other hand, the family history of hypertension was consistently associated with increased transmitral early peak flow velocity and increased transmitral acceleration and deceleration slopes p < 0.05), a pattern suggesting increased left ventricular stiffness. Increased posterior wall thickness and diastolic functional changes may indicate cardiac hypertrophy and decreased left ventricular compliance and precede the development of hypertension in offspring of hypertensive families.

Adult↗
PubMed1995

The Bergen blood pressure study: offspring of two hypertensive parents have significantly higher blood pressures than offspring of one hypertensive and one normotensive parent.

OBJECTIVE: To study blood pressure and antihypertensive drug treatment in subjects with contrasting family histories of hypertension. SUBJECTS AND METHODS: We grouped 520 offspring examined in 1990 (mean +/- SD age 36 +/- 7 years) according to their parents' blood pressure screened in 1963-1964 as offspring of two normotensive (systolic/diastolic blood pressure < 135/70 mmHg) parents (group 1); offspring of one hypertensive (> or = 145/95 mmHg) and one normotensive (<135/70 mmHg) parent (group 2); and offspring of two hypertensive (> or = 140/90 mmHg) parents (group 3). Offspring blood pressure was measured with a conventional mercury sphygmomanometer by one observer. The mean of the last two of three seated measurements was used for analyses. Drug treatment was determined by interview. RESULTS: Mean +/- SD blood pressure was lowest in group 1 (121 +/- 12/72 +/- 10 mmHg), intermediate in group 2 (125 +/- 12/76 +/- 9 mmHg) and highest in group 3 (135 +/- 15/85 +/- 11 mmHg), P<0.01 for each. Of the subjects in groups 1, 2 and 3, 1.3, 2.4 and 11.7%, respectively, were taking antihypertensive drugs (P<0.01). CONCLUSIONS: Screening blood pressure in parents has implications for offspring blood pressure almost 30 years later. Offspring of hypertensive parents have higher blood pressure and are given antihypertensive drugs at higher rates than the offspring of normotensive parents. Also, substantial differences were seen between the offspring of one and of two hypertensive parents. Thus, risk associated with a family history of hypertension varies with the definition of the family history. To obtain maximum contrast in the predisposition to high blood pressure, comparative studies in offspring of hypertensive and normotensive families should be based on blood pressure data from both parents.

Adult↗
PubMed1994

The Bergen Blood Pressure Study: inappropriately low levels of circulating atrial natriuretic peptide in offspring of hypertensive families.

Plasma atrial natriuretic peptide (ANP), plasma and 24-h urine catecholamines, plasma renin activity (PRA), and serum aldosterone were studied in offspring of hypertensive and normotensive families [n = 82; age 37 +/- 7 years (mean +/- SD)]. Despite higher age, higher blood pressure, and higher urine excretion of catecholamines--all of which are factors associated with increased ANP levels--the mean basal plasma ANP concentration tended to be lower in offspring of hypertensive than normotensive families. The same pattern was found in all age-tertiles, and the between-group difference was statistically significant in subjects aged 34-39 years (p < 0.01). Also, the family history of hypertension was associated with low ANP levels after covariate adjustment (p < 0.05). The 24-h urine excretion of epinephrine and norepinephrine tended to be higher in offspring of hypertensive than normotensive families while the morning venous plasma levels were similar. The ratio between venous plasma ANP and norepinephrine was lower in offspring of hypertensive than normotensive families (p < 0.05). PRA, serum aldosterone level, and 24-h urine excretion of dopamine did not differ significantly between groups. Inappropriately low basal plasma ANP concentrations and low plasma ANP/norepinephrine ratios may be related to the development of essential hypertension in offspring of hypertensive families.

Adult↗
PubMed1994

[Effects of shenyan yiqiye on experimental membranous glomerulonephritis in rabbits].

The cationic bovine serum albumin (C-BSA) was used for duplicating experimental animal model of membranous glomerulonephritis with chronic renal failure. Shenyan Yiqiye (SYYQY) was adopted for treatment. The results showed that, in the therapeutic group, the urine protein and serum creatinine were reduced as compared with those in pathological group, P < 0.01. The parameter of morphometric analysis of glomeruli such as mean diameter, mean perimeter, mean surface area, mean volume, mean cross sectional area were all decreased, P < 0.01, the number of glomerular proliferative cells and thickness of glomerular capillary wall were all attenuated, P < 0.01, as compared with those in the pathological group. It suggested that SYYQY might alleviate the glomeruli lesions and benefit the renal functions.

Animals↗
PubMed1994

The Bergen Blood Pressure Study. Estimated prevalence of postural hypotension is influenced by the alerting reaction to blood pressure measurement.

The prevalence of postural hypotension, defined as a > or = 20 mmHg decline in SBP from the sitting to the standing position, was studied in 430 subjects aged 67.2 +/- 6.8 years (mean +/- SD). Before the subjects assumed the upright position, three sitting measurements were performed. The difference between the first sitting and standing recording revealed a postural hypotension prevalence of 18.9%. However, when the mean of the two last sitting recordings was used as baseline, only 4.9% of the subjects experienced a > or = 20 mmHg drop in SBP on standing. It is well documented that the alerting reaction to conventional sphygmomanometry causes the BP to rise and that BP decreases spontaneously with repeated measurements. When postural hypotension is based on the difference between the first sitting and the standing recording, the change in BP is not caused by the change in posture alone but reflects the effect of repeated measurements and the regression-towards-the-mean-phenomenon as well. Consequently, the prevalence of postural hypotension is overestimated. Repeated baseline recordings are encouraged in the assessment of postural hypotension.

Aged↗
PubMed1993

[How much is the decrease in blood pressure shown by repeated measurements during the same examination?].

The recommendations for blood pressure determination by sphygmomanometer encourage repeated measurements. In 430 subjects aged 56-87 years, three recordings were obtained at one minute intervals. On average, the blood pressure decreased 10/3 mm Hg from the first to the third recording (p < 0.001). The decrease was more pronounced in hypertensives (12/4 mmHg) than in normotensives (7/2 mm Hg) (p < 0.01), but was little influenced by sex, age, or body mass. A change of 10/3 mm Hg is relevant with respect to the risk of cardiovascular disease, diagnosis of hypertension, and antihypertensive therapy. Also, repeated measurements may reduce the number of falsely positive hypertensives, and is recommended as the standard procedure in conventional blood pressure determination.

Aged↗
PubMed1993

The Bergen blood pressure study: sodium intake and ambulatory blood pressure in offspring of hypertensive and normotensive families.

Sodium intake, estimated by the 24-h urine sodium excretion, was assessed in 39 offspring of hypertensive families and 37 offspring of normotensive families. The family history of hypertension or normotension was defined according to parental BP data from two surveys conducted 27 years apart. Urine-sodium excretion was similar in offspring of hypertensive and normotensive families, averaging 136 and 137 mmol/24 h, respectively. Monitored by non-invasive methodology in the urine sampling period, the average 24-h ambulatory blood pressure (BP) was approximately 10/10 mmHg higher in offspring of hypertensive than normotensive families. The clinically and statistically significant differences in BP between groups could not be explained by differences in sodium intake. After adjustment for confounding variables, the BP was not associated with the sodium excretion in the material as a whole or in either offspring group.

Adult↗
PubMed1993

The Bergen Blood Pressure Study: blood pressure changes, target organ damage and mortality in subjects with high and low blood pressure over 27 years.

Based on the Bergen population screening in 1963-64, 344 married couples (688 subjects), then aged 30-69 years, were included for studies in families with a history of hypertension or normotension. In 1990 430 subjects were available to a follow-up examination. The present paper describes 27-year mortality, blood pressure (BP) changes, cardiovascular disease and target organ damage in this population. In males who were hypertensive by the 1963-64 screening BP, the all-cause 27-year mortality was three times higher than in initially normotensive males (p < 0.05). From 1963-64 to 1990, the systolic BP was generally increased, whereas the diastolic BP was decreased in initially hypertensive and increased in initially normotensive subjects. In subjects who were hypertensive in 1963-64, the relative risk of hypertension in 1990 was more than seven times higher than in initially normotensive subjects (p < 0.05), cardiovascular events were reported more often (p < 0.001), and the mean electrocardiographic left ventricular voltage was higher (p < 0.01). Proteinuria was more frequent in initially hypertensive than normotensive males (p < 0.01). In summary, hypertension defined by a single BP recording at the 1963-64 screening was a risk factor for hypertension, cardiovascular morbidity and, for males, all-cause mortality 27 years later. With respect to offspring studies, our findings substantiate the classification of hypertensive and normotensive families. From 1963-64 to 1990, the BP status had changed in several couples, and the long observation period seems mandatory if a reliable definition of the family history of hypertension or normotension is to be obtained.

Adult↗
PubMed1993

The Bergen Blood Pressure Study: ambulatory blood pressure in subjects with an accurately defined family history of hypertension or normotension.

24-hour ambulatory blood pressure (BP) was monitored by non-invasive methods in 42 offspring of hypertensive families (age [mean (SD1)] 40(7) years) and 38 offspring of normotensive families (age 33(6) years). The family history was defined according to parental BP data from two surveys conducted 27 years apart. Casual BP was 137(17)/84(12) mmHg in offspring of hypertensive families and 117(9)/69(6) mmHg in offspring of normotensive families (difference: p < 0.001). Average 24-h BP was 123(10)/74(6) mmHg and 113(8)/65(5) mmHg, respectively (difference: p < 0.001). The systolic and diastolic BP difference of approximately 10 mmHg was observed between the groups throughout the monitoring period. Hypertension--defined according to a recent meta-analysis as an average 24-h BP > or = 139/87 mmHg--was found in 6 offspring of hypertensive families and in no offspring of normotensive families (p < 0.05). The 24-h systolic and diastolic BP load--the percentage of readings above 140/90 mmHg (day-time) and 120/80 mmHg (night-time)--was higher in offspring of hypertensive than normotensive families (27%/17% vs. 7%4%; p < 0.001). After adjustment for intrafamilial covariation, age, and other possibly confounding variables, the differences between the groups remained. The present findings suggest that BP in subjects with a family history of hypertension is elevated on a permanent basis, and not only when it is measured in the doctor's office.

Adult↗