Distinct Cyclosporin A Doses Are Required to Enhance Bone Formation Induced by Cyclic and Rest-Inserted Loading in the Senescent Skeleton

Age-related decline in periosteal adaptation negatively impacts the ability to utilize exercise to enhance bone mass and strength in the elderly. We recently observed that in senescent animals subject to cyclically applied loading, supplementation with Cyclosporin A (CsA) substantially enhanced the periosteal bone formation rates to levels observed in young animals. We therefore speculated that if the CsA supplement could enhance bone response to a variety of types of mechanical stimuli, this approach could readily provide the means to expand the range of mild stimuli that are robustly osteogenic at senescence. Here, we specifically hypothesized that a given CsA supplement would enhance bone formation induced in the senescent skeleton by both cyclic (1-Hz) and rest-inserted loading (wherein a 10-s unloaded rest interval is inserted between each load cycle). To examine this hypothesis, the right tibiae of senescent female C57BL/6 mice (22 Mo) were subjected to cyclic or rest-inserted loading supplemented with CsA at 3.0 mg/kg. As previously, we initially found that while the periosteal bone formation rate (p.BFR) induced by cyclic loading was enhanced when supplemented with 3.0 mg/kg CsA (by 140%), the response to rest-inserted loading was not augmented at this CsA dosage. In follow-up experiments, we observed that while a 30-fold lower CsA dosage (0.1 mg/kg) significantly enhanced p.BFR induced by rest-inserted loading (by 102%), it was ineffective as a supplement with cyclic loading. Additional experiments and statistical analysis confirmed that the dose-response relations were significantly different for cyclic versus rest-inserted loading, only because the two stimuli required distinct CsA dosages for efficacy. While not anticipated a priori, clarifying the complexity underlying the observed interaction between CsA dosage and loading type holds potential for insight into how bone response to a broad range of mechanical stimuli may be substantially enhanced in the senescent skeleton.     

Sideways walking: preferred is slow,slow is optimal,and optimal is expensive

When humans wish to move sideways, they almost never walk sideways, except for a step or two; they usually turn and walk facing forward. Here, we show that the experimental metabolic cost of walking sideways, per unit distance, is over three times that of forward walking. We explain this high metabolic cost with a simple mathematical model; sideways walking is expensive because it involves repeated starting and stopping. When walking sideways, our subjects preferred a low natural speed, averaging 0.575 m s⁻¹ (0.123 s.d.). Even with no prior practice, this preferred sideways walking speed is close to the metabolically optimal speed, averaging 0.610 m s⁻¹ (0.064 s.d.). Subjects were within 2.4% of their optimal metabolic cost per distance. Thus, we argue that sideways walking is avoided because it is expensive and slow, and it is slow because the optimal speed is low, not because humans cannot move sideways fast.     

Protective Association of Tumor Necrosis Factor Superfamily 15 (TNFSF15) Polymorphic Haplotype with Ulcerative Colitis and Crohn's Disease in an Indian Population

Background

Tumor necrosis factor superfamily (TNFSF) proteins are involved in the genesis of inflammatory bowel disease (IBD). We examined the association of seven single nucleotide polymorphisms (SNP) in the TNFSF15 gene with Crohn''s disease (CD) and ulcerative colitis (UC) in the Indian population.

Methods

Seven SNPs in the TNFSF15 gene (rs10114470, rs3810936, rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487) were genotyped in 309 CD patients, 330 UC patients and 437 healthy controls using the Sequenom iPLEX MassArray platform. Disease associations were evaluated for allelotypes and for genotypes.

Results

The minor T alleles and the TT genotypes of rs10114470 and rs3810936 were significantly protectively associated with both CD and UC. The CC genotype of rs6478108, AA genotype of rs4263839, the AA genotype of rs6478109, the TT genotype of rs7848647 and the CC genotype of rs7869487 were all protectively associated with CD but not with UC. Two haplotype blocks could be discerned, one where SNPs rs10114470 and rs3810936 were in tight LD (D′ = 0.8) and the other where rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487 were in tight LD (D′ 0.92–1.00). The second block of haplotypes were not associated with CD or with UC. The first block of haplotypes was very significantly associated with both CD and UC.

Conclusions

Strong associations exist between TNFSF15 gene polymorphisms and IBD (both CD and UC) in the Indian population.     

Therapeutic Sesamol Attenuates Monocrotaline-Induced Sinusoidal Obstruction Syndrome in Rats by Inhibiting Matrix Metalloproteinase-9

We investigated the therapeutic effect of sesamol against monocrotaline-induced sinusoidal obstruction syndrome (SOS) in rats. Male Sprague–Dawley rats were gavaged with a single dose of monocrotaline (90 mg/kg) to induce SOS. Sesamol (5, 10, 20, and 40 mg/kg) was subcutaneously injected 24 h after monocrotaline treatment. Control rats were given saline only. Aspartate transaminase, alanine transaminase, mast cells, CD 68⁺ Kupffer cells, neutrophils, myeloperoxidase, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), laminin, and collagen were assessed 48 h after monocrotaline treatment. All tested parameters, except for TIMP-1, laminin, and collagen, were significantly higher in monocrotaline-treated rats than in control rats, and, except for TIMP-1, laminin, and collagen, significantly lower in sesamol-treated rats than in monocrotaline-treated rats. In addition, liver pathology revealed that sesamol offered significant protection against SOS. We conclude that a single dose of sesamol therapeutically attenuated SOS by decreasing the recruitment of inflammatory cells, downregulating MMP-9, and upregulating TIMP-1 expression.     

<Emphasis Type="Italic">Sphingomonas rosea</Emphasis> sp. nov. and <Emphasis Type="Italic">Sphingomonas swuensis</Emphasis> sp. nov., rosy colored <Emphasis Type="Italic">β</Emphasis>-glucosidase-producing bacteria isolated from soil

Two strains PB196^T and PB62^T of Gram-negative, non-motile, and non-spore-forming bacteria, were isolated from soil in South Korea and characterized to determine their taxonomic positions. 16S rRNA gene sequence analysis showed that the two strains belonged to the genus Sphingomonas. The highest degree of sequence similarity of strain PB196^T was found with PB62^T (98.9%), Sphingomonas humi PB323^T (98.9%), Sphingomonas kaistensis PB56^T (98.2%), and Sphingomonas astaxanthinifaciens TDMA-17^T (98.0%). The highest degree of sequence similarity of strain PB62^T was found with Sphingomonas humi PB323^T (98.8%), Sphingomonas astaxanthinifaciens TDMA-17^T (98.2%), and Sphingomonas kaistensis PB56^T (98.1%). Chemotaxonomic data revealed that they possessed ubiquinone-10 (Q-10) as common in the genus Sphingomonas, that the predominant fatty acids were summed feature 7 (C_18:1 ω7c/ω9t/ω12t), summed feature 4 (C_16:1 ω7c/C_15:0 iso 2OH), C_16:0, and C_17:1 ω6c, and that they contained sphingoglycolipid, phosphatidylglycerol (PG), and phosphatidyle-thanolamine (PE) in common but they showed difference for diphosphatidylglycerol (DPG). Based on these data, PB196^T (=KCTC 12339^T =JCM 16604^T) and PB62^T (=KCTC 12336^T =JCM 16605^T =KEMB 9004-005^T) should be classified as type strains of two novel species, for which the names Sphingomonas rosea sp. nov. and Sphingomonas swuensis sp. nov. are proposed, respectively.     

Pigmentiphaga soli sp. nov., a bacterium isolated from soil

Strain BS12^T, a Gram-negative motile bacterium, was isolated from soil in South Korea and characterized to determine its taxonomic position. Phylogenetic analyses based on the 16S rRNA gene sequence revealed that the strain belonged to the family Alcaligenaceae in the class Betaproteobacteria. The highest degree of sequence similarities of strain BS12^T were found with Pigmentiphaga litoralis JSM 061001^T (98.3%), Pigmentiphaga daeguensis K110^T (98.2%), and Pigmentiphaga kullae K24^T (98.1%). Chemotaxonomic data revealed that strain BS12^T possessed ubiquinone-8, which is common in the family Alcaligenaceae, and the predominant fatty acids were C_16:0, C_17:0 cyclo, summed feature 3 (C_16:1 ω6c/ω7c), and summed feature 8 (C_18:1 ω6c/ω7c). The major polar lipids of strain BS12^T were phosphatidylethanolamine and phosphatidylglycerol. Based on these data, BS12^T (=KCTC 23577^T =JCM 17666^T =KEMB 9004-082^T) should be classified as a type strain of a novel species, for which the name Pigmentiphaga soli sp. nov. is proposed.