Increased polyamines as protective disease modifiers in congenital muscular dystrophy.

Most Mendelian disorders, including neuromuscular disorders, display extensive clinical heterogeneity that cannot be solely explained by primary genetic mutations. This phenotypic variability is largely attributed to the presence of disease modifiers, which can exacerbate or lessen the severity and progression of the disease. LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a fatal degenerative muscle disease resulting from mutations in the LAMA2 gene encoding Laminin-α2. Progressive muscle weakness is predominantly observed in the lower limbs in LAMA2-CMD patients, whereas upper limbs muscles are significantly less affected. However, very little is known about the molecular mechanism underlying differential pathophysiology between specific muscle groups. Here, we demonstrate that the triceps muscles of the dy2j/dy2j mouse model of LAMA2-CMD demonstrate very mild myopathic findings compared with the tibialis anterior (TA) muscles that undergo severe atrophy and fibrosis, suggesting a protective mechanism in the upper limbs of these mice. Comparative gene expression analysis reveals that S-Adenosylmethionine decarboxylase (Amd1) and Spermine oxidase (Smox), two components of polyamine pathway metabolism, are downregulated in the TA but not in the triceps of dy2j/dy2j mice. As a consequence, the level of polyamine metabolites is significantly lower in the TA than triceps. Normalization of either Amd1 or Smox expression in dy2j/dy2j TA ameliorates muscle fibrosis, reduces overactive profibrotic TGF-ß pathway and leads to improved locomotion. In summary, we demonstrate that a deregulated polyamine metabolism is a characteristic feature of severely affected lower limb muscles in LAMA2-CMD. Targeted modulation of this pathway represents a novel therapeutic avenue for this devastating disease.

Nutrition, thyroid function and basal metabolism of the Evenki of central Siberia.

Considerable research has shown that indigenous circumpolar populations have elevated basal metabolic rates (BMR). Such elevations are likely promoted by changes in thyroid hormone levels; however, to date, this link between thyroid function and variation in BMR has not been explicitly demonstrated in an indigenous northern group. Thus, the purpose of this paper is to examine 1) the influence of dietary and nutritional factors on variation in thyroid hormone levels, and 2) the influence of thyroid levels on BMR in a sample of indigenous Siberian herders (the Evenki). Measures of body size and composition, dietary intake, thyroid hormones (total and free T3 and T4), thyroid stimulating hormone (TSH) and BMR were obtained for 60 adult subjects (19 males; 41 females) ranging in age from 18-56 years. Thyroid hormone levels in the Evenki were significantly correlated with measures of dietary intake and body composition. Among men, total T3 levels were positively correlated with body weight and fat-free mass (FFM), and negatively correlated with percent body fat; free T4 levels were positively correlated with dietary energy, protein and fat consumption. Among wo-men, there were no clear associations between body composition and thyroid levels; however, dietary energy and protein intakes were po-sitively correlated with total T4 and free T3 levels, respectively. Variation in thyroid hormone levels was associated with differences in BMR. In both sexes, deviations from predicted BMR were positively correlated with free T4 levels. These results demonstrate a link between thyroid hormones and elevated BMR in an indigenous circumpolar population. Further, they show the importance of dietary and nutritional factors for influencing thyroid function and, in turn, metabolic rates among such northern groups.

Underestimation of daily energy expenditure with the factorial method: implications for anthropological research.

Under field conditions, total daily energy expenditure (TDEE) has generally been estimated using time allocation techniques (the factorial method). However, recent work suggests that the factorial method underestimates TDEE relative to newer, more accurate methods such as doubly labelled water (DLW) and heart-rate (HR) monitoring. This study compares estimates of TDEE obtained by the factorial and HR-monitoring methods for a sample of 61 indigenous (Evenki; 17 males, 44 females) and 32 nonindigenous ("Russian"; 10 males, 22 females) subjects from three communities in Central Siberia. Energy expenditures obtained from the two methods were significantly correlated (r = 0.495; P < 0.0001), but the factorial method significantly underestimated TDEE relative to the HR-monitoring technique (8.95 +/- 2.73 vs. 8.25 +/- 1.34 MJ/d; P < 0.005). Interpopulational analyses of data compiled from this and other studies indicate that the factorial method consistently underestimates TDEE relative to DLW and HR monitoring and that the magnitude of underestimation increases with expenditure levels. Indeed, among sedentary populations, factorial estimates of TDEE converge on those of the other methods, whereas at high activity levels the disparity is quite large. These results imply that the daily energy requirements of many subsistence-level populations have been underestimated, thus providing an overly favorable picture of energy balance. Moreover, it is likely that underrepresentation of TDEE is most problematic in rural societies of the developing world which tend to have high activity levels and great risk of malnutrition.

Recent fertility and mortality trends among aboriginal and nonaboriginal populations of central Siberia.

We examine mortality and fertility patterns of aboriginal (primarily Evenki and Keto) and Russian (i.e., nonaboriginal) populations from the Baykit District of Central Siberia for the period 1982-1994. Mortality rates in the aboriginal population of Baykit are substantially greater than those observed in the Russians and are comparable to levels recently reported for other indigenous Siberian groups. Infant mortality rates average 48 per 1000 live births among Baykit aboriginals, three times greater than the Russians of the district (15 per 1000 births) and more than double the rates for Inuit and Indian populations of Canada. Similarly, crude death rates of the Baykit aboriginals are twice as high as those observed in either the Baykit Russians or the Canadian aboriginal populations (13 vs 6-7 deaths per 1000 individuals). Birth rates of the indigenous population of Baykit are higher than those of the Russians (33 vs. 15 births per 1000 individuals) but are comparable to those of Canadian aboriginal groups. Violence and accidents are the leading causes of adult male mortality in both ethnic groups, whereas circulatory diseases have emerged as the prime cause of death in women. The greater male mortality resulting from violence and accidents is a widely observed cross-cultural phenomenon. The emergence of circulatory diseases as a major mortality risk for women, however, appears to be linked to specific lifestyle changes associated with Soviet reorganization of indigenous Siberian societies. Marked declines in mortality and increases in fertility were observed in the Baykit aboriginal population during the mid to late 1980s with the government's implementation of anti-alcohol policies. The decline in mortality, however, was largely erased during the early 1990s, as the region became increasingly isolated and marginalized following the collapse of the Soviet Union. Demographic trends in the Baykit District suggest that because the indigenous groups have become more isolated, many are returning to a more traditional subsistence lifestyle.

PIP: This study compares fertility and mortality patterns among the aboriginal and Russian population in the Evenk Autonomous Region in Siberia. Data were obtained from birth and death records at Baykit Hospital during 1982-94 for the population of the district capital at Baykit and nine isolated rural villages. The indigenous population are semi-subsistence reindeer herders. Cause of death data were obtained from a subsample of 164 persons (101 aboriginals and 24 Russians) from Surinda, Poligus, and Sulamai villages. Findings indicate that aboriginal populations had higher mortality rates. Infant mortality was three times higher than in the Russian population at 48.2 infant aboriginal deaths per 1000 births. The crude death rate among aboriginals was double that of Russians at 12.9 deaths per 1000 aboriginals. The crude birth rate was 33 per 1000 aboriginals. The rate of natural increase was an estimated 2% annually among aboriginals and 1% among Russians. Infant mortality and crude death rates among aboriginals were twice as high as among aboriginals in Canada. Canadian and Siberian aboriginal crude birth rates were similar. In both Russian and aboriginal groups, violent and accidental deaths showed strong gender differences. 56% of male aboriginals and 59% of male Russians died from accidents and violence, while only 31% of aboriginal women and 29% of Russian women did. Most Russian accidental and violent deaths were due to asphyxia and poisoning, while most aboriginal accidental and violent deaths were due to gunshot trauma, in part due to alcohol consumption. About 33% of deaths among aboriginal women and 29% among Russian women were due to circulatory diseases. Russian mortality has remained stable over the last 13 years. Aboriginal mortality and fertility fluctuated. The Russian population grew more rapidly over the past 13 years, but levels varied between villages and between villages and Baykit.

Structural features in the 3' external transcribed spacer affecting intragenic processing of yeast rRNA.

A highly conserved extended hairpin structure in the 3' external transcribed spacer (3' ETS) region of nascent eukaryotic rRNA transcripts is essential for the maturation of the large ribosomal subunit RNAs (5.8 S and 25 to 28 S rRNAs). Systematic changes were introduced into this structure by PCR-mediated mutagenesis and the mutant rDNAs were expressed in vivo to determine the structural features that are essential for rRNA maturation. Changes in the lower half of the stem or the large loop at the end had little or no effect on the maturation of either the 5.8 S or 25 S rRNA, but changes that disrupted secondary structure in the upper half of this stem had equal and dramatic effects on both RNAs. When the RNA stem was incubated with a cellular protein extract, gel retardation studies indicated that the stem forms a ribonucleoprotein complex, and a comparison with mutant RNA indicated that protein binding could be compromised by changes that were critical for rRNA maturation. Sequence comparisons with other spacer regions as well as snRNAs reveal some structural analogy, which, when taken together with the mutational studies, raise the possibility that this hairpin functions during RNA processing in a manner that may be analogous with that of free snRNPs.